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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 -
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 -
Clinical and Translational Medicine Jan 2022Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between...
BACKGROUND
Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non-coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP-based chemotherapy in GC remain under-investigated. This study was designed to explore the critical chemoresistance-related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC.
METHODS
Chemoresistance-related lncRNAs were identified through microarray and verified through a quantitative real-time polymerase chain reaction (qRT-PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull-down assays. Co-immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post-modification. The effects of LINC00942 (LNC942) and MSI2 on DDP-based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo.
RESULTS
LNC942 was found to be up-regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up-regulated the MSI2 expression by preventing its interaction with SCF E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c-Myc mRNA in an N6-methyladenosine (m A)-dependent manner. As a potential m A recognition protein, MSI2 stabilized c-Myc mRNA with m A modifications. Moreover, inhibition of the LNC942-MSI2-c-Myc axis was found to restore chemosensitivity both in vitro and in vivo.
CONCLUSIONS
These results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942-MSI2-c-Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance.
Topics: Cisplatin; Drug Resistance; Genes, myc; Humans; RNA, Long Noncoding; RNA-Binding Proteins; Stomach Neoplasms
PubMed: 35073459
DOI: 10.1002/ctm2.703 -
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 -
Theranostics 2022KRAS mutation is the most frequent oncogenic aberration in colorectal cancer (CRC). The molecular mechanism and clinical implications of KRAS mutation in CRC remain...
KRAS mutation is the most frequent oncogenic aberration in colorectal cancer (CRC). The molecular mechanism and clinical implications of KRAS mutation in CRC remain unclear and show high heterogeneity within these tumors. We harnessed the multi-omics data (genomic, transcriptomic, proteomic, and phosphoproteomic etc.) of KRAS-mutant CRC tumors and performed unsupervised clustering to identify proteomics-based subgroups and molecular characterization. In-depth analysis of the tumor microenvironment by single-cell transcriptomic revealed the cellular landscape of KRAS-mutant CRC tumors and identified the specific cell subsets with KRAS mutation. Integrated multi-omics analyses separated the KRAS-mutant tumors into two distinct molecular subtypes, termed KRAS-M1 (KM1) and KRAS-M2 (KM2). The two subtypes had a similar distribution of mutated residues in KRAS (G12D/V/C etc.) but were characterized by distinct features in terms of prognosis, genetic alterations, microenvironment dysregulation, biological phenotype, and potential therapeutic approaches. Proteogenomic analyses revealed that the EMT, TGF-β and angiogenesis pathways were enriched in the KM2 subtype and that the KM2 subtype was associated with the mesenchymal phenotype-related CMS4 subtype, which indicated stromal invasion and worse prognosis. The KM1 subtype was characterized predominantly by activation of the cell cycle, E2F and RNA transcription and was associated with the chromosomal instability (CIN)-related ProS-E proteomic subtype, which suggested cyclin-dependent features and better survival outcomes. Moreover, drug sensitivity analyses based on three compound databases revealed subgroup-specific agents for KM1 and KM2 tumors. This study clarifies the molecular heterogeneity of KRAS-mutant CRC and reveals new biological subtypes and therapeutic possibilities for these tumors.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; Genes, ras; Humans; Mutation; Proteomics; Proto-Oncogene Proteins p21(ras); Tumor Microenvironment
PubMed: 35836817
DOI: 10.7150/thno.73089