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EBioMedicine Jan 2022c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is... (Review)
Review
c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Genes, myc; Humans; Neoplasms; Proto-Oncogene Proteins c-myc
PubMed: 34942444
DOI: 10.1016/j.ebiom.2021.103756 -
Nature Reviews. Clinical Oncology Jan 2022The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or... (Review)
Review
The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
Topics: Genes, myc; Humans; Immune Evasion; Neoplasms; Oncogenes
PubMed: 34508258
DOI: 10.1038/s41571-021-00549-2 -
BMJ (Clinical Research Ed.) Dec 2020Cancers of unknown primary (CUPs) are histologically confirmed, metastatic malignancies with a primary tumor site that is unidentifiable on the basis of standard... (Review)
Review
Cancers of unknown primary (CUPs) are histologically confirmed, metastatic malignancies with a primary tumor site that is unidentifiable on the basis of standard evaluation and imaging studies. CUP comprises 2-5% of all diagnosed cancers worldwide and is characterized by early and aggressive metastasis. Current standard evaluation of CUP requires histopathologic evaluation and identification of favorable risk subtypes that can be more definitively treated or have superior outcomes. Current standard treatment of the unfavorable risk subtype requires assessment of prognosis and consideration of empiric chemotherapy. The use of molecular tissue of origin tests to identify the likely primary tumor site has been extensively studied, and here we review the rationale and the evidence for and against the use of such tests in the assessment of CUPs. The expanding use of next generation sequencing in advanced cancers offers the potential to identify a subgroup of patients who have actionable genomic aberrations and may allow for further personalization of therapy.
Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Circulating Tumor DNA; Gene Expression Profiling; Genes, erbB-1; Genes, erbB-2; High-Throughput Nucleotide Sequencing; Humans; Lymph Nodes; Mammography; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Mutation; Neoplasms, Unknown Primary; Occult Blood; Physical Examination; Physical Functional Performance; Positron Emission Tomography Computed Tomography; Proto-Oncogene Proteins B-raf; Real-Time Polymerase Chain Reaction; Risk Assessment; Tomography, X-Ray Computed
PubMed: 33288500
DOI: 10.1136/bmj.m4050 -
Nature Reviews. Cancer Aug 2020The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to... (Review)
Review
The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2-p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.
Topics: Animals; Biological Evolution; Evolution, Molecular; Genes, BRCA1; Genes, p53; Genes, ras; Humans; Li-Fraumeni Syndrome; Mutation; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Stem Cells; Stress, Physiological; Tumor Suppressor Protein p53; Vertebrates
PubMed: 32404993
DOI: 10.1038/s41568-020-0262-1 -
International Journal of Cancer May 2020Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme... (Review)
Review
Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme polymorphisms have been identified to increase the risk for smokers, recent epidemiological data suggest even sex-specificity as a new and additional factor. Obviously, women have a higher risk to develop lung cancer upon smoking than men. Overall, the odds ratio to develop lung cancer was almost three times greater for women than for men, DNA adduct levels were higher among females than in males and mutations in the tumor suppressor gene p53 and the proto-oncogene K-RAS were more frequently found in women than in men. A growing number of studies suggest that the interaction between tobacco carcinogens and endogenous and exogenous sex steroids may be important. Women taking hormone replacement therapy (HRT) or oral contraceptives experienced to have an increased lung cancer incidence. Epidemiologic data on HRT show a significant association between both a younger median age at lung cancer diagnosis and a shorter median survival time. Another clue is the significantly higher number of lung cancer diagnosed women who are largely premenopausal in comparison to diagnosed men in the same age or women with shorter menstrual cycles. Finally, the Coronary Drug Project (men who received estrogen preparations to reduce future cardiac events) was stopped when increased lung cancer mortality was observed in the estrogen therapy group. The present review provides a short overview and discussion on lung cancer risk and the impact thereon of sex.
Topics: Carcinogens; Female; Hormone Replacement Therapy; Humans; Incidence; Lung Neoplasms; Male; Proto-Oncogene Mas; Proto-Oncogenes; Risk Factors; Sex Factors; United States
PubMed: 31583690
DOI: 10.1002/ijc.32716 -
Cell May 2022Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal...
Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.
Topics: Animals; Genes, ras; Mice; Neoplasms; Phylogeny; Exome Sequencing
PubMed: 35523183
DOI: 10.1016/j.cell.2022.04.015 -
Cancer Metastasis Reviews Dec 2020RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are... (Review)
Review
RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are pancreatic, colorectal, lung adenocarcinomas and urogenital cancers. KRAS mutation frequencies are relatively stable worldwide in various cancer types with the one exception of lung adenocarcinoma. The frequencies of KRAS variant alleles appears cancer type specific, reflecting the various carcinogenic processes. In addition to point mutation KRAS, allelic imbalances are also frequent in human cancers leading to the predominance of a mutant allele. KRAS mutant cancers are characterized by typical, cancer-type-specific co-occurring mutations and distinct gene expression signatures. The heterogeneity of KRAS mutant primary cancers is significant, affecting the variant allele frequency, which could lead to unpredictable branching development in metastases. Selection of minute mutant subclones in the primary tumors or metastases during target therapies can also occur frequently in lung or colorectal cancers leading to acquired resistance. Ultrahigh sensitivity techniques are now routinely available for diagnostic purposes, but the proper determination of mutant allele frequency of KRAS in the primary or metastatic tissues may have larger clinical significance.
Topics: Animals; Genes, ras; Humans; Molecular Epidemiology; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 32725342
DOI: 10.1007/s10555-020-09915-5 -
Cancer Cell Oct 2022KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death...
KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.
Topics: Decitabine; Genes, ras; Humans; Ligands; Lung Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 36150391
DOI: 10.1016/j.ccell.2022.08.015 -
Cell Research Jan 2023Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS...
Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-Kras; Trp53 mice. Mechanistically, RASON directly binds to KRAS and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRAS in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.
Topics: Humans; Animals; Mice; RNA, Long Noncoding; Proto-Oncogene Proteins p21(ras); Genes, ras; Fibroblasts; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Guanosine Triphosphate; Mutation
PubMed: 36241718
DOI: 10.1038/s41422-022-00726-7 -
Science (New York, N.Y.) Oct 2021Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report...
Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)–dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.
Topics: Animals; Cell Cycle Checkpoints; Cell Line; Cellular Senescence; Chemokines, CXC; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Genes, ras; Hepatocytes; Humans; Immunologic Surveillance; Macrophages; Mice; Mice, Transgenic; Proto-Oncogene Proteins p21(ras); Retinoblastoma Protein; Stress, Physiological; T-Lymphocytes, Cytotoxic; Transcription, Genetic
PubMed: 34709885
DOI: 10.1126/science.abb3420