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Leukemia Mar 2024AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in...
AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
Topics: Humans; Animals; Mice; Transcription Factors; MDS1 and EVI1 Complex Locus Protein; Nuclear Proteins; Antineoplastic Agents; Leukemia, Myeloid, Acute; Epigenesis, Genetic; Proto-Oncogenes; Bromodomain Containing Proteins; Cell Cycle Proteins
PubMed: 38086946
DOI: 10.1038/s41375-023-02108-3 -
Current Problems in Cancer Apr 2024Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell... (Review)
Review
Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1-2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. While first-generation RET inhibitors have become part of the standard of care for RET-fusion positive NSCLC, a new challenge has emerged: acquired resistance to RET inhibitors. RET resistance is a complex phenomenon that can manifest as either on-target or off-target resistance. Numerous studies have been conducted to identify the mechanisms behind this resistance. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.
Topics: Humans; Proto-Oncogene Proteins c-ret; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Proto-Oncogene Mas; Protein Kinase Inhibitors; Drug Resistance, Neoplasm; Mutation; Molecular Targeted Therapy; Antineoplastic Agents
PubMed: 38494387
DOI: 10.1016/j.currproblcancer.2024.101074 -
Cureus Jan 2024Molecular biology shines a light of hope amid the complex terrain of cancer, bringing revolutionary approaches to cancer treatment. Instead of providing a synopsis, this... (Review)
Review
Molecular biology shines a light of hope amid the complex terrain of cancer, bringing revolutionary approaches to cancer treatment. Instead of providing a synopsis, this review presents an engaging story that sheds light on the genetic nuances controlling the course of cancer. This review goes beyond just listing genetic alterations to examine the complex interactions that lead to oncogene activation, exploring particular triggers such as viral infections or proto-oncogene mutations. A comprehensive grasp of the significant influence of oncogenes is possible through the classification and clarification of their function in various types of cancer. Furthermore, the role of tumor suppressor genes in controlling cell division and preventing tumor growth is fully explained, providing concrete examples and case studies to ground the conversation and create a stronger story. This study highlights the practical applications of molecular biology and provides a comprehensive overview of various detection and treatment modalities. It emphasizes the effectiveness of RNA analysis, immunohistochemistry, and next-generation sequencing (NGS) in cancer diagnosis and prognosis prediction. Examples include the individualized classification of breast cancers through RNA profiling, the use of NGS to identify actionable mutations such as epidermal growth factor receptor and anaplastic lymphoma kinase in lung cancer, and the use of immunohistochemical staining for proteins such as Kirsten rat sarcoma viral oncogene to guide treatment decisions in colorectal cancer. This paper carefully examines how molecular biology is essential to creating new strategies to fight this difficult and widespread illness. It highlights the exciting array of available therapeutic approaches, offering concrete instances of how clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR-Cas9), targeted pharmaceuticals, immunotherapy, and treatments that induce apoptosis are driving a paradigm shift in cancer care. The revolutionary CRISPR-Cas9 system takes center stage, showcasing how precise gene editing could transform cancer therapy. This study concludes by fervently highlighting the critical role that molecular biology plays in reducing the complexity of cancer and changing the treatment landscape. It lists accomplishments but also thoughtfully examines cases and findings that progress our search for more precisely customized and effective cancer therapies.
PubMed: 38352075
DOI: 10.7759/cureus.52246 -
Journal of Cellular Physiology May 2024c-Fos, a member of the immediate early gene, serves as a widely used marker of neuronal activation induced by various types of brain damage. In addition, c-Fos is... (Review)
Review
c-Fos, a member of the immediate early gene, serves as a widely used marker of neuronal activation induced by various types of brain damage. In addition, c-Fos is believed to play a regulatory role in DNA damage repair. This paper reviews the literature on c-Fos' involvement in the regulation of DNA damage repair and indicates that genes of the Fos family can be induced by various forms of DNA damage. In addition, cells lacking c-Fos have difficulties in DNA repair. c-Fos is involved in tumorigenesis and progression as a proto-oncogene that maintains cancer cell survival, which may also be related to DNA repair. c-Fos may impact the repair of DNA damage by regulating the expression of downstream proteins, including ATR, ERCC1, XPF, and others. Nonetheless, the underlying mechanisms necessitate further exploration.
Topics: Humans; DNA Repair; DNA Damage; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos; Animals; Neoplasms
PubMed: 38327128
DOI: 10.1002/jcp.31216 -
Nature Communications Feb 2024The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively...
The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYC but not MYC cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYC murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.
Topics: Humans; Mice; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Proto-Oncogene Proteins c-myc; Genes, myc; Cell Transformation, Neoplastic; Carcinogenesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38302473
DOI: 10.1038/s41467-024-45128-y -
Clinical & Translational Oncology :... Oct 2023The tyrosine kinase Fyn is a member of the SRC family of kinases, and its sustained activation is closely linked to tumor cell migration, proliferation, and cell... (Review)
Review
The tyrosine kinase Fyn is a member of the SRC family of kinases, and its sustained activation is closely linked to tumor cell migration, proliferation, and cell metabolism. Recently, Fyn has been found to be expressed in various tumor tissues, and the expression and function of Fyn vary between tumors, with Fyn acting as an oncogene to promote proliferation and metastasis in some tumors. This article summarizes the recent studies on the role of Fyn in different human tumors, focusing on the role of Fyn in melanoma, breast cancer, glioma, lung cancer, and peripheral T-cell lymphoma in order to provide a basis for future research and targeted therapy in different human tumors.
Topics: Humans; Melanoma; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-fyn
PubMed: 37093456
DOI: 10.1007/s12094-023-03167-9 -
Cancer Chemotherapy and Pharmacology Aug 2023Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug...
A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.
PURPOSE
Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.
METHODS
Patients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.
RESULTS
Twenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.
CONCLUSION
Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug-drug interactions.
TRIAL REGISTRATION ID
NCT03065387.
Topics: Humans; Middle Aged; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Protein Kinase Inhibitors; Genes, erbB; Mutation; ErbB Receptors; Nausea; Diarrhea; Mitogen-Activated Protein Kinase Kinases; Receptor, ErbB-2
PubMed: 37314501
DOI: 10.1007/s00280-023-04545-4 -
Life Science Alliance Nov 2023Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate...
Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate remains unknown. Here, we used the in vitro differentiation of human pluripotent stem cells into cardiomyocytes to study the role of c-JUN. Surprisingly, the knockout of c-JUN improved cardiomyocyte generation, as determined by the number of TNNT2+ cells. ATAC-seq data showed that the c-JUN defect led to increased chromatin accessibility on critical regulatory elements related to cardiomyocyte development. ChIP-seq data showed that the knockout c-JUN increased RBBP5 and SETD1B expression, leading to improved H3K4me3 deposition on key genes that regulate cardiogenesis. The c-JUN KO phenotype could be copied using the histone demethylase inhibitor CPI-455, which also up-regulated H3K4me3 levels and increased cardiomyocyte generation. Single-cell RNA-seq data defined three cell branches, and knockout c-JUN activated more regulons that are related to cardiogenesis. In summary, our data demonstrated that c-JUN could regulate cardiomyocyte cell fate by modulating H3K4me3 modification and chromatin accessibility and shed light on how c-JUN regulates heart development in humans.
Topics: Animals; Humans; Mice; Cell Differentiation; Chromatin; Genes, jun; Human Embryonic Stem Cells; Myocytes, Cardiac; Proto-Oncogene Proteins c-jun
PubMed: 37604584
DOI: 10.26508/lsa.202302121 -
Life Sciences Jun 2024E74-like factor 3 (ELF3) is an important member of the E-twenty-six (ETS) transcription factor family. ELF3 is expressed in various types of cells and regulates a... (Review)
Review
E74-like factor 3 (ELF3) is an important member of the E-twenty-six (ETS) transcription factor family. ELF3 is expressed in various types of cells and regulates a variety of biological behaviors, such as cell proliferation, differentiation, apoptosis, migration, and invasion, by binding to DNA to regulate the expression of other genes. In recent years, studies have shown that ELF3 plays an important role in the occurrence and development of many tumors and inflammation and immune related diseases. ELF3 has different functions and expression patterns in different tumors; it can function as a tumor suppressor gene or an oncogene, highlighting its dual effects of tumor promotion and inhibition. ELF3 also affects the levels of tumor immunity-related cytokines and is involved in the regulation and expression of multiple signaling pathways. In tumor therapy, ELF3 is a complex and multifunctional gene and has become a key focus of targeted treatment research. An in-depth study of the biological function of ELF3 can help to elucidate its role in biological processes and provide ideas and a basis for the development and clinical application of ELF3-related therapeutic methods. This review introduces the structure and physiological and cellular functions of the ELF3 gene, summarizes the mechanisms of action of ELF3 in different types of malignant tumors and its role in immune regulation, inflammation, etc., and discusses treatment methods for ELF3-related diseases, providing significant reference value for scholars studying the ELF3 gene and related diseases.
Topics: Humans; Neoplasms; Transcription Factors; DNA-Binding Proteins; Animals; Proto-Oncogene Proteins c-ets; Gene Expression Regulation, Neoplastic; Inflammation
PubMed: 38614305
DOI: 10.1016/j.lfs.2024.122637 -
Pathology, Research and Practice Aug 2023Cancer genes are largely categorized into tumor suppressor gene (TSG) and proto-oncogene, but many have dual activities depending on the cellular context. In the present...
Cancer genes are largely categorized into tumor suppressor gene (TSG) and proto-oncogene, but many have dual activities depending on the cellular context. In the present study, we analyzed DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F genes known to possess the dual activities in sporadic colon cancers (CCs). By the mutation analysis, we identified DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F frameshift mutations in 2, 2, 3, 3, and 1 CCs in instability-high (MSI-H) cases (1.1-3.2% of MSI-H CCs), respectively, but not microsatellite stable (MSS) cases. One CC showed regional heterogeneous mutations (RHM) of ESRP1 mutation. Immunohistochemistry identified protein expression of ESRP1, MTSS1, and ADAMTS1 in the CCs, revealing that approximately 30% of CCs lost the protein expression irrespective of the MSI status. Our study showed that dual TSG and proto-oncogene genes DYRK1B, ESRP1, MTSS1, ADAMTS1, and INPP5F harbored low incidences of inactivating mutations, but that the protein losses were frequent in CCs. Our study suggests a possibility that the dual-function genes could be altered mainly at the expression level, which might contribute to CC pathogenesis.
Topics: Humans; Colorectal Neoplasms; Genes, Tumor Suppressor; Mutation; Frameshift Mutation; Colonic Neoplasms; Microsatellite Instability; Proto-Oncogenes; Microsatellite Repeats; Microfilament Proteins; Neoplasm Proteins
PubMed: 37429176
DOI: 10.1016/j.prp.2023.154659