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Finding Summary
AKT1 encodes an intracellular serine/threonine kinase and is one of three members of the AKT gene family. AKT activation promotes cell survival via inhibition of apoptosis and also contributes to cell proliferation through several interactions with the cell cycle machinery; inappropriate activation of AKT can therefore lead to tumor formation 59. Missense mutations and in-frame duplications that occur in the pleckstrin homology (PH) domain of AKT1, as seen here, have been shown to transform cells and activate AKT signaling and are therefore, considered to be oncogenic 60-66.
Potential Treatment Strategies (Breast Carcinoma- 05.08.2020)
On the basis of clinical evidence, AKT1 activation may predict sensitivity to AKT inhibitors, such as ipatasertib and capivasertib. In a Phase 1 study, a patient with HER2-negative metastatic breast cancer harboring an AKT1 E17K mutation had a complete metabolic response to ipatasertib44. In a Phase 1 trial of capivasertib in patients with solid
tumors bearing the AKT1 E17K activating mutation, 24% (11/45) of patients had a PR and
82% (37/45) of patients experienced tumor shrinkage 45. The FAKTION Phase 2 trial of capivasertib plus fulvestrant, compared to placebo plus fulvestrant, in women with ER+/HER2- breast cancer after relapse or disease progression on an aromatase inhibitor reported a significantly higher ORR (41% vs. 12%, p=0.002) and significantly longer PFS (10.3 months vs. 4.8 months, p=0.004) in the capivasertib arm than the placebo arm; notably, presence of PIK3CA hotspot mutations or loss of PTEN expression did not affect the efficacy of capivasertib plus fulvestrant 46. For patients with metastatic triple-
negative breast cancer harboring PIK3CA/AKT1/ PTEN alterations, Phase 2 studies have reported improved PFS from the addition of either ipatasertib (9.0 vs. 4.9 months, HR = 0.44) or capivasertib (9.3 vs. 3.7 months, HR = 0.30) to paclitaxel, compared with paclitaxel and placebo 47. Additionally, 2/7 patients with AKT1 E17K mutations treated with the AKT inhibitor ARQ 092 (1 with breast cancer, 1 with follicular lymphoma) achieved PR, 2 obtained minor responses (parotid cancer, 19.3% tumor reduction; endometrial cancer, 17.5% reduction), and 3 achieved SD (ovarian cancer, neuroendocrine cancer, and meningioma, being 120-277 days on therapy) 48. A patient with AKT1 E17K-mutated thymoma was reported to achieve a 26% tumor regression for 17 months after treatment with an mTOR inhibitor 49, suggesting AKT1 activating alterations may be sensitive to mTOR inhibitors such as everolimus and temsirolimus. AKT1 amplification and/or AKT1 protein expression may be associated with resistance to chemotherapeutic agents, including cisplatin, in some cancer types, such as ovarian cancer and lung cancer 50-54.
Frequency & prognosis
In the TCGA dataset, AKT1 mutations have been reported in approximately 2% of all breast carcinomas; the E17K mutation accounts for the majority of these mutations28. In one study of breast carcinomas, AKT1 mutations were detected in 3% (1/31) of invasive ductal carcinomas but not in any invasive mucinous carcinomas (0/35)55. Another study reported AKT1 mutations in 7% (8/108) of patients with metastatic breast cancer 56. A clinicogenomic registry study for patients with estrogen receptor-positive metastatic breast cancer reported increased rates of metastasis to the liver (32.7% vs. 22.8%, p<0.001) and lymph node (31.4% vs. 24.8%, p=0.026) for patients with AKT1 E17K-mutated tumors relative to wild-type AKT1 tumors; however, median OS did not significantly differ with respect to AKT1 mutation status (24.1 vs. 29.9 months, p=0.98, HR=1.0)57. A retrospective study reported a significant association of reduced survival and AKT1 copy number gain (HR=3.89) or high AKT1 mRNA expression (HR=3.93-6.1) for patients with triple-negative breast cancer basal-like 2 subtype 58.
ABL1, also known as Abelson tyrosine-protein kinase 1, is a human gene that encodes a protein called c-Abl. The ABL1 gene is located on chromosome 9 and plays a crucial role in cell signaling and regulation of various cellular processes, including cell growth, differentiation, and apoptosis (programmed cell death).
The c-Abl protein is a tyrosine kinase, meaning it catalyzes the transfer of phosphate groups to tyrosine residues on target proteins, thereby regulating their activity. The activity of c-Abl is tightly regulated in normal cells to prevent uncontrolled cell growth and maintain cellular homeostasis.
Mutations in the ABL1 gene can lead to abnormal activation of the c-Abl protein, which may contribute to the development of certain types of cancers, particularly in leukemia. The fusion of the ABL1 gene with the BCR (breakpoint cluster region) gene, resulting in the BCR-ABL fusion gene, is associated with chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL).
Research on ABL1 and related proteins is ongoing, and targeted therapies have been developed to specifically inhibit the abnormal activity of the BCR-ABL fusion protein in CML and certain forms of ALL. These targeted therapies have significantly improved the prognosis and outcomes for patients with these specific types of leukemia.
ALK stands for Anaplastic Lymphoma Kinase, which is a gene that encodes a receptor tyrosine kinase (RTK) protein called ALK. The ALK gene is located on chromosome 2 in humans. The ALK protein plays a crucial role in cell growth, differentiation, and survival, particularly during the development of the nervous system.
Mutations or genetic alterations in the ALK gene can lead to abnormal activation of the ALK protein, which has been implicated in the development of certain cancers. The most well-known association is with anaplastic large cell lymphoma (ALCL), a type of non-Hodgkin lymphoma. In some cases of ALCL, the ALK gene undergoes a fusion with other partner genes, leading to the expression of abnormal ALK fusion proteins with constitutive kinase activity, promoting cancer cell growth and survival.
Moreover, ALK gene fusions have also been identified in other cancers, such as a subset of non-small cell lung cancers (NSCLC) and neuroblastoma (a type of childhood cancer). These discoveries have led to the development of targeted therapies, such as ALK inhibitors, which specifically block the activity of abnormal ALK proteins and have shown promising results in treating ALK-positive cancers.
ARAF, also known as A-Raf proto-oncogene serine/threonine-protein kinase, is a human gene that encodes a protein called A-Raf. A-Raf is a member of the Raf family of kinases and plays a role in cellular signaling pathways, particularly the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway.
The MAPK/ERK pathway is a crucial signaling cascade involved in various cellular processes, including cell growth, proliferation, differentiation, and survival. When activated, A-Raf phosphorylates and activates MEK (MAPK/ERK kinase), which, in turn, activates ERK1/2 (extracellular signal-regulated kinase 1/2). The activated ERK1/2 can then translocate to the nucleus and regulate the expression of specific genes, leading to various cellular responses.
Abnormal activation of the MAPK/ERK pathway, including A-Raf, has been implicated in several cancers. Mutations or dysregulation of A-Raf can lead to uncontrolled cell growth and contribute to tumorigenesis. However, compared to other members of the Raf kinase family (B-Raf and C-Raf), A-Raf mutations are less commonly found in cancer.
Research on A-Raf and its role in cancer is ongoing, and understanding its function is crucial for developing targeted therapies that may inhibit the dysregulated MAPK/ERK pathway in specific cancer types.
The ATM gene (Ataxia Telangiectasia Mutated) plays a significant role in both hereditary and sporadic cancers. As mentioned earlier, the ATM gene is involved in repairing damaged DNA and maintaining genomic stability. Mutations in the ATM gene can lead to the development of certain types of cancer, as well as influence the response to cancer treatments.
Hereditary Cancer Predisposition: Inherited mutations in the ATM gene can increase an individual’s risk of developing certain types of cancer. For example, individuals with Ataxia Telangiectasia (caused by mutations in both copies of the ATM gene) have a significantly elevated risk of developing cancers like leukemia, lymphoma, and breast cancer.
Sporadic Cancers: Even in individuals without a known family history of Ataxia Telangiectasia or other inherited cancer predisposition syndromes, somatic mutations (mutations acquired during a person’s lifetime) in the ATM gene can occur in cancer cells. These mutations can disrupt the normal DNA repair mechanisms, leading to genomic instability and contributing to tumor development and progression.
Response to Cancer Treatment: The status of the ATM gene can also influence how cancer cells respond to certain treatments. For instance, tumors with defective ATM functions may be more sensitive to certain types of cancer therapies, such as radiotherapy and some chemotherapy drugs. This sensitivity occurs because cancer cells with impaired ATM function have a reduced ability to repair DNA damage caused by these treatments, making them more susceptible to cell death.
However, on the other hand, the presence of ATM mutations can also lead to resistance to specific cancer treatments, such as poly (ADP-ribose) polymerase (PARP) inhibitors, which exploit DNA repair deficiencies in cancer cells. In some cases, tumors with ATM mutations may be less responsive to these targeted therapies.
Due to the complex interplay between the ATM gene, DNA repair, and cancer development, the study of ATM and its implications in cancer is an active area of research. Scientists and clinicians are working to better understand the precise role of ATM in different cancer types, identify potential therapeutic targets, and develop personalized treatment approaches based on the genetic profile of individual tumors.
BRAF stands for “B-Raf proto-oncogene, serine/threonine kinase.” It is a human gene that encodes a protein called B-Raf. The BRAF gene is an essential component of the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) signaling pathway.
The MAPK/ERK pathway plays a critical role in transmitting signals from the cell surface to the nucleus, regulating various cellular processes such as cell growth, proliferation, differentiation, and survival. When activated, the B-Raf protein phosphorylates and activates MEK (MAPK/ERK kinase), which in turn activates ERK1/2 (extracellular signal-regulated kinase 1/2). The activated ERK1/2 can then enter the nucleus and regulate the expression of specific genes, leading to various cellular responses.
Mutations in the BRAF gene can lead to abnormal activation of the MAPK/ERK pathway, which is associated with the development of several cancers. The most well-known BRAF mutation is the V600E mutation, in which a valine (V) is substituted for glutamic acid (E) at position 600 of the B-Raf protein. This mutation results in a constitutively active B-Raf kinase, leading to uncontrolled cell growth and proliferation.
BRAF mutations are particularly prevalent in certain types of cancers, most notably melanoma, a type of skin cancer. They are also found in a subset of colorectal cancers, papillary thyroid cancers, and other malignancies. The discovery of BRAF mutations in various cancers has led to the development of targeted therapies known as BRAF inhibitors, which specifically target the abnormal activity of the mutant BRAF protein.
BRAF-targeted therapies, often used in combination with other treatments, have shown promising results in the treatment of BRAF-mutant cancers and have improved the prognosis for patients with these specific cancer types. However, like many targeted therapies, resistance to these drugs can develop over time, and research continues to find ways to overcome resistance and improve patient outcomes.
BRCA1 stands for “Breast Cancer Gene 1.” It is a human gene located on chromosome 17 and is one of the most well-known tumor suppressor genes. Mutations in the BRCA1 gene are associated with an increased risk of breast and ovarian cancer, as well as other types of cancer.
The BRCA1 gene is responsible for producing a protein that plays a crucial role in repairing damaged DNA and maintaining genomic stability. When functioning normally, the BRCA1 protein helps to repair breaks in DNA and prevent harmful mutations from accumulating in the cell.
However, certain mutations in the BRCA1 gene can disrupt its normal function, leading to an increased susceptibility to cancer. Women with certain harmful mutations in the BRCA1 gene have a significantly higher lifetime risk of developing breast and ovarian cancer compared to the general population. Men with BRCA1 mutations are also at an increased risk of developing breast cancer and may have an elevated risk of prostate and other cancers.
BRCA1-associated breast and ovarian cancers tend to occur at younger ages and may be more aggressive compared to non-hereditary forms of these cancers.
Genetic testing can identify harmful BRCA1 mutations in individuals and families with a history of breast, ovarian, and other cancers. Identifying such mutations can be crucial in managing cancer risk and informing personalized prevention and treatment strategies.
There are preventive measures and risk-reduction options available for individuals with BRCA1 mutations, such as increased surveillance, prophylactic surgeries, and targeted therapies. Additionally, advancements in research have led to targeted therapies for certain types of BRCA1-associated cancers, like PARP inhibitors.
It’s essential to note that BRCA1 is just one of several genes associated with hereditary breast and ovarian cancer risk. The BRCA2 gene is another well-known gene in this context. Genetic testing can help identify mutations in both BRCA1 and BRCA2 and guide appropriate medical management for individuals and families at risk.
BRCA2, like BRCA1, stands for “Breast Cancer Gene 2.” It is a human gene located on chromosome 13 and is also a tumor suppressor gene. Mutations in the BRCA2 gene are associated with an increased risk of breast, ovarian, and other cancers.
Similar to BRCA1, the BRCA2 gene encodes a protein that plays a critical role in DNA repair and maintaining genomic stability. The BRCA2 protein is involved in the repair of double-strand DNA breaks, ensuring the proper functioning of cells and preventing harmful mutations from accumulating.
Individuals with certain harmful mutations in the BRCA2 gene have an elevated risk of developing breast and ovarian cancer, as well as an increased risk of male breast cancer and other cancers such as pancreatic cancer and prostate cancer.
BRCA2-associated breast and ovarian cancers tend to occur at younger ages and may have distinct characteristics compared to non-hereditary forms of these cancers.
Genetic testing can identify harmful BRCA2 mutations in individuals and families with a history of breast, ovarian, and other cancers. The identification of such mutations can guide medical management decisions, including increased surveillance, preventive surgeries, and personalized treatment plans.
Just like BRCA1, BRCA2 mutations have implications for cancer risk management and targeted therapies. For instance, individuals with BRCA2 mutations may be eligible for targeted therapies, such as PARP inhibitors, in certain types of cancers.
It is essential to recognize that BRCA1 and BRCA2 are just two of the several genes associated with hereditary breast and ovarian cancer risk. Other genes, such as PALB2 and TP53, are also known to increase cancer susceptibility.
BRIP1 (also known as BACH1 or FANCJ) is a human gene that plays a crucial role in DNA repair and maintenance of genomic stability. It is a member of the Fanconi Anemia (FA) pathway, which is a complex network of proteins involved in repairing DNA damage and preventing the accumulation of harmful mutations.
The BRIP1 gene encodes a protein called BRIP1/FANCJ helicase, which has helicase activity, meaning it can unwind and process DNA structures during the DNA repair process. The BRIP1 protein is involved in the repair of DNA double-strand breaks and helps ensure the stability of the genome.
Mutations in the BRIP1 gene have been associated with an increased risk of certain cancers, particularly breast and ovarian cancer. Like BRCA1 and BRCA2 mutations, BRIP1 mutations can lead to a higher lifetime risk of developing these cancers, often at younger ages. The risk associated with BRIP1 mutations may vary depending on the specific type and location of the mutation.
BRIP1 is also associated with an increased risk of a condition called Fanconi Anemia, which is a rare genetic disorder characterized by bone marrow failure, congenital anomalies, and an elevated risk of cancer. In Fanconi Anemia, the FA pathway is impaired, leading to problems in DNA repair and genomic stability.
Genetic testing can identify harmful BRIP1 mutations in individuals and families with a history of breast, ovarian, and other cancers. Identifying such mutations can be important in managing cancer risk and informing personalized prevention and treatment strategies.
As with any genetic risk for cancer, it is essential to seek guidance from a qualified genetic counselor or healthcare professional who specializes in cancer genetics. They can provide personalized risk assessment, discuss available risk-reduction strategies, and offer support for making informed medical decisions based on an individual’s specific genetic profile and family history.
BTK, in the context of cancer treatment, stands for Bruton’s tyrosine kinase, as previously mentioned. It is an enzyme that plays a crucial role in B-cell signaling in the immune system. Inhibition of BTK has emerged as an important therapeutic strategy in the treatment of certain B-cell malignancies.
BTK inhibitors are a class of targeted therapies that work by blocking the activity of the BTK enzyme, which is essential for the survival and proliferation of B-cell lymphoma and leukemia cells. By inhibiting BTK, these drugs disrupt the signaling pathways that support the growth and survival of cancerous B cells, leading to their destruction.
Ibrutinib was the first BTK inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It has since been approved for various other B-cell malignancies, including Waldenström macroglobulinemia and marginal zone lymphoma. Other BTK inhibitors, such as acalabrutinib and zanubrutinib, have also been developed and approved for certain B-cell cancers.
BTK inhibitors have demonstrated significant clinical benefits in patients with B-cell malignancies, providing improved response rates, progression-free survival, and overall survival. They have become a critical part of the treatment armamentarium for these cancers, both as first-line therapy and for patients who have relapsed or are resistant to other treatments.
As with any cancer treatment, BTK inhibitors may have side effects, and their use is generally tailored to the specific patient’s condition. Common side effects may include bleeding problems, bruising, diarrhea, and an increased risk of infections.
CCNE1 stands for “Cyclin E1,” which is a human gene that encodes the protein Cyclin E1. Cyclins are a family of proteins that play a crucial role in regulating the cell cycle, the process by which cells grow and divide.
Cyclin E1 is a regulatory protein that forms a complex with cyclin-dependent kinases (CDKs) and helps drive the cell cycle progression from the G1 phase to the S phase. During the G1 phase, the cell prepares for DNA synthesis (replication), and Cyclin E1-CDK complex is involved in promoting the initiation of DNA replication.
Abnormalities in the regulation of Cyclin E1 can contribute to uncontrolled cell growth and division, a hallmark of cancer. Overexpression of CCNE1 and its association with increased CDK activity have been observed in various types of cancer, including breast cancer, ovarian cancer, and lung cancer. In some cases, the amplification or upregulation of the CCNE1 gene leads to higher levels of Cyclin E1, promoting cell cycle progression even in the absence of proper growth signals.
The dysregulation of Cyclin E1 has been linked to aggressive tumor behavior and poor prognosis in certain cancers. Therefore, CCNE1 has been recognized as a potential oncogene and a target for cancer therapy. Research efforts are ongoing to better understand the role of Cyclin E1 in cancer development and identify potential targeted therapies that could block its function or interfere with the Cyclin E1-CDK interactions.
CDK12 stands for “Cyclin-Dependent Kinase 12,” which is a member of the cyclin-dependent kinase (CDK) family of proteins. CDKs are enzymes that play a crucial role in cell cycle regulation and are involved in controlling various cellular processes, including cell growth, division, and DNA repair.
CDK12 is unique among the CDK family members because it has been found to have a specific role in regulating transcription, which is the process of synthesizing RNA from DNA templates. CDK12 interacts with another protein called Cyclin K, forming a complex that regulates the expression of genes involved in DNA repair and maintaining genomic stability.
Mutations or alterations in the CDK12 gene have been identified in various cancers, including ovarian cancer, breast cancer, prostate cancer, and others. These alterations can affect the normal function of CDK12 and may contribute to tumor development and progression.
CDK12 alterations have gained attention in cancer research because they may be associated with increased sensitivity to certain cancer therapies. In tumors with CDK12 mutations, the DNA repair pathway may be impaired, making cancer cells more reliant on other DNA repair mechanisms for survival. This vulnerability has led to the investigation of CDK12 inhibitors as potential targeted therapies for cancers with CDK12 alterations. Clinical trials are ongoing to assess the efficacy of CDK12 inhibitors in specific cancer types, and research in this area is actively evolving.
CDK4 stands for “Cyclin-Dependent Kinase 4,” which is a member of the cyclin-dependent kinase (CDK) family of proteins. CDKs are enzymes that play a critical role in regulating the cell cycle, the process by which cells grow and divide.
CDK4, along with its regulatory partner, Cyclin D1, forms a complex that controls the progression of cells from the G1 phase to the S phase of the cell cycle. During the G1 phase, cells prepare for DNA synthesis (replication), and the CDK4-Cyclin D1 complex is involved in promoting the cell’s entry into the S phase, where DNA replication occurs.
Abnormalities in the CDK4 gene or its regulatory partner Cyclin D1 can lead to uncontrolled cell growth and contribute to the development of cancer. For example, certain genetic alterations, such as amplification or overexpression of CDK4 and Cyclin D1, have been found in various cancers, including certain types of breast cancer and melanoma.
In particular, CDK4 is of interest in the context of cancers that lack specific genetic alterations in other CDK-related genes, such as CDK6 or Cyclin D1. In such cases, targeting CDK4 has been explored as a potential therapeutic strategy.
CDK4 inhibitors are a class of targeted therapies that have been developed to block the activity of CDK4 and disrupt the cell cycle progression of cancer cells. By inhibiting CDK4, these drugs can lead to cell cycle arrest and prevent cancer cells from dividing and proliferating.
Palbociclib, ribociclib, and abemaciclib are examples of CDK4/6 inhibitors that have been approved for the treatment of certain hormone receptor-positive and HER2-negative breast cancers. These inhibitors have shown promising results in clinical trials and have become an important component of treatment for specific breast cancer subtypes
CDKN2A stands for “Cyclin-Dependent Kinase Inhibitor 2A,” which is a human gene that encodes two important tumor suppressor proteins, p16INK4a and p14ARF (also known as p19ARF in mice). These proteins play critical roles in regulating the cell cycle and preventing uncontrolled cell growth and tumor formation.
1) p16INK4a (p16):
p16INK4a is a cyclin-dependent kinase inhibitor that functions as a negative regulator of the cell cycle. It specifically inhibits the activity of CDK4 and CDK6, which are involved in promoting cell cycle progression from the G1 phase to the S phase. By inhibiting CDK4 and CDK6, p16INK4a helps to arrest the cell cycle and prevent excessive cell division. Loss or inactivation of p16INK4a can lead to uncontrolled cell growth, contributing to the development of various cancers, including melanoma and pancreatic cancer.
2) p14ARF (p19ARF in mice):
p14ARF is another product of the CDKN2A gene and plays a distinct role in tumor suppression. Unlike p16INK4a, p14ARF is not directly involved in cell cycle regulation. Instead, it functions as an activator of the p53 tumor suppressor protein. p53 is a critical transcription factor that regulates various cellular processes, including DNA repair, cell cycle arrest, and apoptosis (programmed cell death). Activation of p14ARF stabilizes and activates p53, leading to the induction of cell cycle arrest and apoptosis in response to cellular stress or DNA damage. Loss of p14ARF can impair the p53 pathway and disrupt the cellular response to DNA damage, increasing the risk of cancer development.
Mutations or alterations in the CDKN2A gene can lead to the inactivation or loss of p16INK4a and/or p14ARF function, resulting in a higher susceptibility to various cancers. Familial melanoma and pancreatic cancer syndromes, among others, are associated with inherited mutations in the CDKN2A gene.
Genetic testing for CDKN2A mutations can be important for individuals with a family history of melanoma, pancreatic cancer, or other related cancers, as it may help inform cancer risk assessment and management strategies. Close monitoring, early detection, and potential preventive measures can be considered for individuals at increased risk due to CDKN2A mutations.
CHEK1, also known as CHK1 (Checkpoint Kinase 1), is a human gene that encodes the protein CHK1. CHK1 is a serine/threonine kinase that plays a critical role in cell cycle checkpoint regulation and the cellular response to DNA damage.
When DNA damage occurs, such as during replication stress or exposure to genotoxic agents (e.g., radiation or chemotherapeutic drugs), CHK1 is activated to halt the cell cycle progression. CHK1 activation allows the cell to repair the damaged DNA before continuing with cell division. This checkpoint mechanism helps to maintain genomic stability and prevent the propagation of genetic mutations, which could lead to cancer development.
CHK1 is part of the DNA damage response (DDR) pathway, which includes various other checkpoint proteins and DNA repair factors. It interacts with other proteins involved in DNA repair, cell cycle control, and apoptosis (programmed cell death) to coordinate the appropriate cellular response to DNA damage.
Given its central role in the DDR, CHK1 has emerged as an attractive target for cancer therapy. Inhibition of CHK1 can sensitize cancer cells to DNA-damaging treatments, such as radiation or certain chemotherapeutic agents. By blocking CHK1, cancer cells become more vulnerable to the accumulation of DNA damage, leading to their death or growth arrest.
Several CHK1 inhibitors have been developed and studied in preclinical and clinical trials for cancer treatment. These inhibitors are being investigated both as monotherapies and in combination with other cancer treatments. The goal is to enhance the efficacy of standard cancer therapies and overcome resistance mechanisms in certain tumors.
CHEK2, also known as CHK2 (Checkpoint Kinase 2), is a human gene that encodes the protein CHK2. Similar to CHK1, CHK2 is a serine/threonine kinase that plays a critical role in the cellular response to DNA damage and replication stress.
When DNA damage occurs, CHK2 is activated as part of the DNA damage response (DDR) pathway. It is primarily activated in response to double-strand breaks in the DNA. CHK2 acts downstream of another kinase called ATM (Ataxia Telangiectasia Mutated), which initiates the DDR cascade in response to DNA damage.
Activated CHK2, in turn, phosphorylates and activates various downstream targets, including p53, BRCA1, and CDC25 family members. These phosphorylation events lead to cell cycle arrest, DNA repair, and apoptosis (programmed cell death), depending on the extent and type of DNA damage.
The activation of CHK2 serves as a surveillance mechanism to ensure that damaged DNA is appropriately repaired before cell division proceeds. By halting the cell cycle and promoting DNA repair or apoptosis, when necessary, CHK2 helps to prevent the propagation of damaged DNA and the development of cancer.
Mutations in the CHEK2 gene have been identified in certain hereditary cancer syndromes, particularly in families with an increased risk of breast cancer and other cancers. Some CHEK2 mutations are associated with an elevated risk of breast, prostate, and other cancers, albeit with lower penetrance compared to mutations in genes like BRCA1 and BRCA2.
Research on CHK2 and its implications in cancer risk is ongoing, and genetic testing for CHEK2 mutations may be considered for individuals with a family history of breast or other relevant cancers. Genetic counseling can help assess cancer risk based on family history and genetic testing results, and appropriate screening and risk-reduction strategies can be discussed.
EGFR stands for “Epidermal Growth Factor Receptor,” which is a cell surface receptor that plays a crucial role in cell growth, proliferation, and survival. It is a member of the ErbB family of receptor tyrosine kinases.
EGFR is activated when it binds to specific ligands, such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and others. Upon ligand binding, EGFR undergoes a series of conformational changes that lead to the activation of its intrinsic tyrosine kinase activity.
The activation of EGFR triggers a signaling cascade involving various downstream signaling pathways, such as the RAS-RAF-MEK-ERK pathway and the PI3K-AKT pathway. These pathways regulate cell growth, proliferation, survival, and differentiation.
Abnormalities in EGFR signaling have been implicated in various cancers. In some cases, cancer cells overexpress EGFR, leading to continuous activation of the receptor and uncontrolled cell growth. EGFR overexpression is particularly well-known in certain types of cancer, such as non-small cell lung cancer (NSCLC), head and neck cancer, and colorectal cancer.
In NSCLC, for example, some tumors harbor specific mutations in the EGFR gene, such as exon 19 deletions or the L858R mutation. These mutations lead to constitutive activation of EGFR and are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (EGFR TKIs), a class of targeted therapies. EGFR TKIs block the tyrosine kinase activity of EGFR, effectively inhibiting downstream signaling and slowing down tumor growth.
EGFR-targeted therapies have become an important part of the treatment for certain cancer types, particularly in patients with specific EGFR mutations or overexpression. In addition to EGFR TKIs, monoclonal antibodies that target the extracellular domain of EGFR have also been developed and approved for use in specific cancer types.
The use of EGFR-targeted therapies is often guided by the presence of specific EGFR alterations in the tumor, as identified through genetic testing or other diagnostic methods. These therapies have shown promising results, but resistance mechanisms can develop over time, and ongoing research aims to address these challenges and improve treatment outcomes.
ERBB2, also known as HER2 (Human Epidermal Growth Factor Receptor 2), is a human gene that encodes the HER2 protein, a member of the ErbB family of receptor tyrosine kinases. Like EGFR (Epidermal Growth Factor Receptor), HER2 is a cell surface receptor that plays a critical role in cell growth, proliferation, and survival.
HER2 is unique among the ErbB family members because it does not have a well-defined ligand that activates it through direct binding. Instead, HER2 can form heterodimers with other members of the ErbB family, such as EGFR (HER1), HER3, and HER4. These heterodimeric complexes transmit signals to the cell, leading to the activation of downstream signaling pathways.
Abnormalities in the HER2 gene, particularly gene amplification or overexpression, have been implicated in various cancers, most notably breast cancer. HER2 gene amplification or overexpression leads to an increased number of HER2 receptors on the cell surface, resulting in enhanced signaling through HER2-containing dimers.
HER2-positive breast cancer is a subtype of breast cancer characterized by the presence of HER2 gene amplification or overexpression. HER2-positive breast cancer tends to be more aggressive and may have a higher risk of recurrence compared to HER2-negative breast cancer. However, the development of targeted therapies has significantly improved the prognosis for patients with HER2-positive breast cancer.
Trastuzumab (Herceptin) was the first targeted therapy developed specifically for HER2-positive breast cancer. Trastuzumab is a monoclonal antibody that targets and blocks the HER2 receptor, inhibiting HER2 signaling and slowing down tumor growth. Trastuzumab has been shown to improve survival and outcomes for patients with HER2-positive breast cancer and is commonly used in combination with chemotherapy in the treatment of this subtype.
Other HER2-targeted therapies, such as pertuzumab (Perjeta) and ado-trastuzumab emtansine (Kadcyla), have also been developed and approved for HER2-positive breast cancer. These targeted therapies, used alone or in combination, have further improved the treatment options and outcomes for patients with HER2-positive breast cancer.
In addition to breast cancer, HER2 overexpression can also occur in other types of cancer, such as gastric cancer. HER2-targeted therapies are being studied and used in these other cancer types as well.
ESR1 stands for “Estrogen Receptor 1,” which is a human gene that encodes the estrogen receptor alpha (ERα) protein. ERα is a nuclear hormone receptor and a member of the steroid hormone receptor superfamily.
The estrogen receptor plays a central role in mediating the effects of the hormone estrogen in various tissues throughout the body. It is predominantly expressed in target tissues, such as the breast, uterus, and bone.
When estrogen binds to ERα, the receptor undergoes a conformational change, allowing it to interact with specific DNA sequences known as estrogen response elements (EREs) within the regulatory regions of target genes. This binding activates or represses the transcription of these target genes, leading to the regulation of various cellular processes, including cell growth, differentiation, and apoptosis.
ERα is particularly important in the context of breast cancer, as it drives the growth of hormone receptor-positive breast cancers. In hormone receptor-positive breast cancer, the cancer cells express estrogen receptors (ER+) and/or progesterone receptors (PR+). These cancers rely on the presence of estrogen to fuel their growth and proliferation.
Hormone therapy, also known as endocrine therapy, is a common treatment for hormone receptor-positive breast cancer. The goal of hormone therapy is to block the binding of estrogen to its receptors or inhibit estrogen production, thereby depriving the cancer cells of estrogen signals and slowing down tumor growth.
Selective Estrogen Receptor Modulators (SERMs) are one class of hormone therapy drugs used to treat hormone receptor-positive breast cancer. SERMs, such as tamoxifen, bind to estrogen receptors and act as competitive inhibitors, blocking estrogen from binding to the receptor. Other hormone therapy drugs, such as aromatase inhibitors (AIs), work by reducing estrogen production in postmenopausal women.
While hormone therapy is highly effective in many cases, some breast cancers may develop resistance to these treatments over time. Research is ongoing to better understand the mechanisms of resistance and develop new strategies to overcome it.
Aside from breast cancer, ERα also plays essential roles in other physiological processes, including bone metabolism and reproductive functions.
EZH2 stands for “Enhancer of Zeste Homolog 2,” which is a human gene that encodes the EZH2 protein. EZH2 is a member of the Polycomb group (PcG) proteins and is a key component of the Polycomb Repressive Complex 2 (PRC2).
The main function of EZH2 is to add methyl groups to histone proteins, specifically to the lysine 27 residue of histone H3 (H3K27). This modification, known as histone H3 lysine 27 trimethylation (H3K27me3), is associated with gene silencing and plays a critical role in regulating gene expression during development and cellular differentiation.
EZH2 is particularly important in the context of epigenetic regulation and gene control. The PRC2 complex, which includes EZH2, contributes to the maintenance of gene repression patterns by placing H3K27me3 marks on specific regions of the genome. These marks are recognized by other proteins that help maintain the genes in a silent or repressed state.
While EZH2 is essential for normal development and tissue differentiation, its dysregulation has been implicated in various diseases, including cancer. In cancer, EZH2 can become overexpressed or mutated, leading to aberrant gene silencing and altered gene expression patterns.
Overexpression of EZH2 is particularly common in certain types of cancer, including various hematological malignancies and solid tumors. In some cases, EZH2 overexpression is associated with more aggressive tumor behavior and poor prognosis.
EZH2 inhibitors have been developed as potential targeted therapies for cancer treatment. These inhibitors work by blocking the catalytic activity of EZH2, preventing it from adding methyl groups to histones and altering gene expression. By inhibiting EZH2, these drugs aim to reverse the epigenetic alterations associated with cancer and potentially slow down tumor growth.
EZH2 inhibitors have shown promise in preclinical studies and early-stage clinical trials for certain types of cancer. However, more research is needed to fully understand the optimal use of EZH2 inhibitors and their potential side effects.
FANCL stands for “Fanconi Anemia Complementation Group L,” which is a human gene associated with Fanconi anemia (FA). Fanconi anemia is a rare genetic disorder characterized by bone marrow failure, congenital malformations, and an increased risk of cancer.
The FANCL gene is part of a group of genes known as the Fanconi anemia complementation group. These genes play essential roles in the repair of DNA damage, particularly the repair of DNA interstrand crosslinks. Interstrand crosslinks are abnormal structures in the DNA that prevent the two strands of the DNA double helix from unwinding and separating during processes such as DNA replication and transcription. Mutations in the FANCL gene, as well as mutations in other Fanconi anemia genes, can impair the DNA repair process, leading to the accumulation of DNA damage and chromosomal instability. This genetic instability is a hallmark of Fanconi anemia and can contribute to the various clinical features of the disorder, including bone marrow failure and an increased risk of cancer, especially leukemia and certain solid tumors.The exact function of the FANCL gene is to encode a protein that is involved in the activation of the Fanconi anemia pathway. This pathway coordinates the repair of DNA crosslinks through a series of complex interactions with other Fanconi anemia proteins.
Diagnosis of Fanconi anemia is typically made based on clinical features, such as bone marrow failure and congenital malformations, and confirmed through genetic testing to identify mutations in one of the Fanconi anemia complementation group genes, including FANCL.
Currently, there is no cure for Fanconi anemia. Treatment is focused on managing the symptoms and complications of the disorder, such as bone marrow transplantation to treat bone marrow failure and regular cancer screenings to detect malignancies at an early stage.
FGFR1 stands for “Fibroblast Growth Factor Receptor 1,” which is a human gene that encodes the FGFR1 protein. FGFR1 is a member of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases.
The fibroblast growth factor (FGF) signaling pathway plays crucial roles in various cellular processes, including cell growth, proliferation, migration, and differentiation. FGFR1 is involved in mediating the cellular response to FGF ligands.
When FGF ligands bind to FGFR1, the receptor undergoes dimerization and autophosphorylation, leading to the activation of its tyrosine kinase activity. This, in turn, triggers downstream signaling cascades involving various signaling molecules, including RAS-MAPK, PI3K-AKT, and STAT pathways. These pathways regulate cell behavior and gene expression, contributing to cellular responses, such as cell proliferation and survival.
Abnormalities in the FGFR1 gene or FGFR1 overexpression have been implicated in various diseases, including certain cancers and developmental disorders.
FGFR1 in Cancer:
In cancer, alterations in FGFR1 can lead to increased signaling through the FGF pathway, promoting cancer cell growth and survival. FGFR1 gene amplification, gene rearrangements, and activating mutations have been identified in different types of cancer, such as lung cancer, breast cancer, and glioblastoma.
FGFR1 alterations, especially gene fusions and activating mutations, have been recognized as potential oncogenic drivers, particularly in subsets of squamous cell lung carcinoma and other malignancies. As such, FGFR1 has become a target for cancer therapy.
FGFR1-Targeted Therapies:
FGFR1-targeted therapies, such as FGFR inhibitors, have been developed to block the activity of FGFR1 and inhibit downstream signaling pathways. These inhibitors are designed to selectively target cancer cells with FGFR1 alterations, sparing normal cells with normal FGFR1 function.
Clinical trials are ongoing to evaluate the efficacy and safety of FGFR inhibitors in patients with FGFR1-altered cancers. The results have been promising, especially in patients whose tumors harbor specific FGFR1 alterations.
FGFR2 stands for “Fibroblast Growth Factor Receptor 2,” which is a human gene that encodes the FGFR2 protein. Like FGFR1, FGFR2 is a member of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases.
The FGFR2 protein functions as a cell surface receptor that mediates the cellular response to fibroblast growth factors (FGFs) and regulates various cellular processes, including cell growth, differentiation, migration, and survival.
When FGF ligands bind to FGFR2, the receptor undergoes dimerization and autophosphorylation, leading to the activation of its tyrosine kinase activity. This initiates a series of downstream signaling cascades involving various intracellular signaling molecules, including RAS-MAPK, PI3K-AKT, and STAT pathways. These pathways regulate gene expression and cell behavior, influencing various cellular responses.
FGFR2 has crucial roles in embryonic development, tissue repair, and homeostasis in adults. However, abnormalities in FGFR2 have been associated with various diseases, including certain developmental disorders and cancers.
FGFR2 in Cancer:
Alterations in FGFR2 have been identified in certain types of cancer, where they may contribute to tumorigenesis and cancer progression. FGFR2 gene amplification, gene fusions, and activating mutations have been reported in various malignancies, such as gastric cancer, breast cancer, cholangiocarcinoma, and endometrial cancer.
In some cancers, specific FGFR2 alterations can act as oncogenic drivers, promoting uncontrolled cell growth and survival. Consequently, FGFR2 has become an attractive target for cancer therapy.
FGFR2-Targeted Therapies:
FGFR2-targeted therapies, including FGFR inhibitors, have been developed to block the activity of FGFR2 and inhibit downstream signaling pathways. These inhibitors aim to selectively target cancer cells with FGFR2 alterations while sparing normal cells with normal FGFR2 function.
Clinical trials are ongoing to assess the efficacy and safety of FGFR inhibitors in patients with FGFR2-altered cancers. Preliminary data from these trials have shown promise, particularly in subsets of patients whose tumors harbor specific FGFR2 alterations.
FGFR3 stands for “Fibroblast Growth Factor Receptor 3,” which is a human gene that encodes the FGFR3 protein. FGFR3 is a member of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases.
The FGFR3 protein serves as a cell surface receptor that plays a pivotal role in mediating the cellular response to fibroblast growth factors (FGFs). FGFs are signaling proteins that regulate various cellular processes, including cell growth, differentiation, migration, and survival.
When FGF ligands bind to FGFR3, the receptor undergoes dimerization and autophosphorylation, which triggers the activation of its tyrosine kinase activity. This activation initiates downstream signaling cascades that involve various intracellular signaling molecules, such as RAS-MAPK, PI3K-AKT, and STAT pathways. These pathways regulate gene expression and control cell behavior, influencing diverse cellular responses.
FGFR3 has roles in embryonic development, tissue repair, and homeostasis in adults. Abnormalities in FGFR3 have been linked to various diseases, including developmental disorders and cancers.
FGFR3 in Developmental Disorders:
Mutations in FGFR3 have been associated with several skeletal dysplasias and chondrodysplasias, which are characterized by abnormal growth and development of bones and cartilage. For example, mutations in FGFR3 are known to cause achondroplasia, the most common form of dwarfism. These mutations result in overactive FGFR3 signaling, leading to impaired skeletal growth.
FGFR3 in Cancer:
FGFR3 alterations are also implicated in certain types of cancer, particularly in urothelial carcinoma (also known as bladder cancer). Activating mutations in FGFR3 have been identified in a subset of urothelial carcinomas. These mutations lead to constitutive activation of FGFR3 and contribute to cancer cell growth and survival.
FGFR3 mutations are more common in non-muscle invasive bladder cancer and are associated with a relatively favorable prognosis compared to bladder cancers without FGFR3 mutations. These mutations have led to the development of targeted therapies for this specific subset of urothelial carcinomas.
FGFR3-Targeted Therapies:
Targeted therapies aimed at inhibiting the abnormal activity of FGFR3 have been explored for the treatment of cancer. FGFR inhibitors have been developed to block the signaling activity of FGFR3 and halt downstream signaling pathways, potentially slowing down tumor growth.
Clinical trials are ongoing to evaluate the efficacy and safety of FGFR inhibitors in patients with FGFR3-altered cancers, particularly in urothelial carcinoma. These inhibitors represent a promising approach for personalized cancer treatment in cases where FGFR3 mutations are present.
FLI1 is a human gene that encodes the FLI1 protein, which belongs to the ETS family of transcription factors. Transcription factors are proteins that regulate the expression of genes by binding to specific DNA sequences and controlling the transcription process.
FLI1 is particularly important in the development and function of blood cells and blood vessels. It plays a role in the formation of blood vessels during embryonic development and contributes to the regulation of genes involved in blood cell differentiation. FLI1 is also known for its involvement in certain types of cancer, most notably Ewing sarcoma, a rare and aggressive type of bone and soft tissue cancer that primarily affects children and young adults.
In Ewing sarcoma, a chromosomal translocation involving the FLI1 gene and another gene (typically the EWSR1 gene) leads to the fusion of the two genes, creating a novel fusion gene. This fusion gene produces a chimeric protein that has aberrant transcriptional activity, promoting the development and progression of Ewing sarcoma.
The FLI1 gene is normally involved in the regulation of cell growth and differentiation. However, in Ewing sarcoma, the fusion protein created by the gene fusion drives uncontrolled cell growth and contributes to tumor formation.
Understanding the role of the FLI1 gene and its fusion counterpart in Ewing sarcoma has led to the development of targeted therapies for this cancer type. Researchers are actively exploring strategies to disrupt the activity of the FLI1 fusion protein and inhibit the signaling pathways it activates.
FLT3 stands for “Fms-Like Tyrosine Kinase 3,” which is a human gene that encodes the FLT3 protein, also known as CD135. FLT3 is a receptor tyrosine kinase that plays a critical role in the development and functioning of hematopoietic stem cells and progenitor cells, which are responsible for generating various blood cell types.
The FLT3 receptor is activated by binding to its ligand, FLT3 ligand (FL), leading to dimerization and autophosphorylation of the receptor’s tyrosine residues. This activation triggers downstream signaling pathways, including the RAS-MAPK and PI3K-AKT pathways, which regulate cell growth, survival, proliferation, and differentiation.
Mutations in the FLT3 gene can have significant implications in hematological malignancies, particularly acute myeloid leukemia (AML). Two main types of FLT3 mutations are of clinical interest:
FLT3 Internal Tandem Duplication (ITD) Mutations: This mutation involves the duplication of a segment within the FLT3 gene, leading to an elongated and constitutively active FLT3 protein. FLT3-ITD mutations are commonly found in AML and are associated with a poor prognosis and a higher risk of relapse.
FLT3 Tyrosine Kinase Domain (TKD) Mutations: These mutations affect the kinase domain of the FLT3 protein, leading to constitutive activation of the receptor. FLT3-TKD mutations are less common than FLT3-ITD mutations but are also associated with adverse outcomes in AML.
The presence of FLT3 mutations in AML has led to the development of targeted therapies aimed at inhibiting FLT3 activity. FLT3 inhibitors, such as midostaurin and gilteritinib, have been developed and approved for the treatment of FLT3-mutated AML. These inhibitors block the aberrant signaling pathways driven by FLT3 mutations, potentially slowing down tumor growth and improving patient outcomes.
FLT3-targeted therapies are typically used in combination with standard chemotherapy for the treatment of FLT3-mutated AML. However, resistance to FLT3 inhibitors can develop over time, prompting ongoing research to address this challenge and improve treatment strategies.
FLT3 stands for “Fms-Like Tyrosine Kinase 3,” which is a human gene that encodes the FLT3 protein, also known as CD135. FLT3 is a receptor tyrosine kinase that plays a critical role in the development and functioning of hematopoietic stem cells and progenitor cells, which are responsible for generating various blood cell types.
The FLT3 receptor is activated by binding to its ligand, FLT3 ligand (FL), leading to dimerization and autophosphorylation of the receptor’s tyrosine residues. This activation triggers downstream signaling pathways, including the RAS-MAPK and PI3K-AKT pathways, which regulate cell growth, survival, proliferation, and differentiation.
Mutations in the FLT3 gene can have significant implications in hematological malignancies, particularly acute myeloid leukemia (AML). Two main types of FLT3 mutations are of clinical interest:
FLT3 Internal Tandem Duplication (ITD) Mutations: This mutation involves the duplication of a segment within the FLT3 gene, leading to an elongated and constitutively active FLT3 protein. FLT3-ITD mutations are commonly found in AML and are associated with a poor prognosis and a higher risk of relapse.
FLT3 Tyrosine Kinase Domain (TKD) Mutations: These mutations affect the kinase domain of the FLT3 protein, leading to constitutive activation of the receptor. FLT3-TKD mutations are less common than FLT3-ITD mutations but are also associated with adverse outcomes in AML.
The presence of FLT3 mutations in AML has led to the development of targeted therapies aimed at inhibiting FLT3 activity. FLT3 inhibitors, such as midostaurin and gilteritinib, have been developed and approved for the treatment of FLT3-mutated AML. These inhibitors block the aberrant signaling pathways driven by FLT3 mutations, potentially slowing down tumor growth and improving patient outcomes.
FLT3-targeted therapies are typically used in combination with standard chemotherapy for the treatment of FLT3-mutated AML. However, resistance to FLT3 inhibitors can develop over time, prompting ongoing research to address this challenge and improve treatment strategies.
HRAS is a human gene that encodes the HRas protein, a member of the Ras family of small GTPases. Ras proteins are essential components of signaling pathways that regulate cell growth, proliferation, differentiation, and survival.
HRas, along with NRas and KRas, is one of the three main isoforms of Ras proteins found in humans. These proteins are involved in transmitting signals from cell surface receptors to the cell’s interior, ultimately influencing various cellular processes.
The Ras proteins cycle between an inactive GDP-bound state and an active GTP-bound state. When activated, Ras proteins transmit signals downstream through various signaling cascades, including the MAPK (Mitogen-Activated Protein Kinase) pathway, which regulates cell growth and proliferation.
Mutations in the HRAS gene, as well as in other Ras family genes, have been implicated in various cancers. These mutations lead to the constitutive activation of Ras proteins, causing abnormal cell signaling and promoting uncontrolled cell growth and tumorigenesis.
HRAS mutations are commonly associated with several types of cancers, including:
Cancers with Neurofibromatosis Type 1 (NF1): Neurofibromatosis Type 1 is a genetic disorder characterized by the development of benign tumors called neurofibromas. A subset of these tumors can progress to malignant peripheral nerve sheath tumors (MPNSTs), which often have HRAS mutations.
Head and Neck Squamous Cell Carcinoma (HNSCC): HRAS mutations are found in a subset of HNSCC cases, contributing to the development and progression of these cancers.
Bladder Cancer: HRAS mutations have been identified in some cases of bladder cancer, particularly in certain histological subtypes.
Other Cancers: HRAS mutations have also been reported in other cancer types, including thyroid cancer, lung cancer, and melanoma.
Targeted therapies aimed at inhibiting the activity of Ras proteins, including HRAs, have been challenging to develop due to the complex and transient nature of Ras activation. However, research into Ras signaling pathways and potential therapeutic strategies is ongoing.
IDH1 stands for “Isocitrate Dehydrogenase 1,” which is a human gene that encodes the IDH1 protein. IDH1 is an enzyme that plays a crucial role in cellular metabolism, specifically in the citric acid cycle (also known as the Krebs cycle) within the mitochondria.
The citric acid cycle is a fundamental metabolic pathway that generates energy by oxidizing acetyl-CoA, a product of carbohydrate, fat, and protein metabolism. IDH1 is responsible for catalyzing the conversion of isocitrate to alpha-ketoglutarate, a step in the citric acid cycle.
Mutations in the IDH1 gene have been implicated in various cancers, most notably in gliomas, a type of brain tumor, and acute myeloid leukemia (AML), a type of blood cancer. These mutations result in a gain-of-function alteration in the enzyme’s activity, leading to the production of an oncometabolite called 2-hydroxyglutarate (2-HG).
The accumulation of 2-HG disrupts cellular metabolism and epigenetic regulation, contributing to the development and progression of cancer. 2-HG inhibits the activity of various enzymes, including DNA and histone demethylases, leading to widespread alterations in DNA and histone methylation patterns. These changes in epigenetic regulation can affect gene expression and cellular differentiation, promoting tumorigenesis.
IDH1 mutations are commonly found in specific subsets of gliomas, particularly in lower-grade gliomas (such as grade II and III gliomas) and secondary glioblastomas (GBM), which arise from the progression of lower-grade gliomas. In AML, IDH1 mutations are found in a subset of patients and are associated with distinct clinical and molecular features.
The identification of IDH1 mutations in certain cancers has led to the development of targeted therapies. Small molecule inhibitors that specifically target the mutant IDH1 enzyme are being studied as potential treatments for patients with IDH1-mutated gliomas and AML. These inhibitors aim to reduce the production of 2-HG and restore normal cellular metabolism and epigenetic regulation.
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