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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 -
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 -
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 -
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 -
Blood Feb 2023Chromosomal rearrangements involving the MDS1 and EVI1 complex locus (MECOM) on chromosome 3q26 define an aggressive subtype of acute myeloid leukemia (AML) that is...
Chromosomal rearrangements involving the MDS1 and EVI1 complex locus (MECOM) on chromosome 3q26 define an aggressive subtype of acute myeloid leukemia (AML) that is associated with chemotherapy resistance and dismal prognosis. Established treatment regimens commonly fail in these patients, therefore, there is an urgent need for new therapeutic concepts that will require a better understanding of the molecular and cellular functions of the ecotropic viral integration site 1 (EVI1) oncogene. To characterize gene regulatory functions of EVI1 and associated dependencies in AML, we developed experimentally tractable human and murine disease models, investigated the transcriptional consequences of EVI1 withdrawal in vitro and in vivo, and performed the first genome-wide CRISPR screens in EVI1-dependent AML. By integrating conserved transcriptional targets with genetic dependency data, we identified and characterized the ETS transcription factor ERG as a direct transcriptional target of EVI1 that is aberrantly expressed and selectively required in both human and murine EVI1-driven AML. EVI1 controls the expression of ERG and occupies a conserved intragenic enhancer region in AML cell lines and samples from patients with primary AML. Suppression of ERG induces terminal differentiation of EVI1-driven AML cells, whereas ectopic expression of ERG abrogates their dependence on EVI1, indicating that the major oncogenic functions of EVI1 are mediated through aberrant transcriptional activation of ERG. Interfering with this regulatory axis may provide entry points for the development of rational targeted therapies.
Topics: Humans; Animals; Mice; DNA-Binding Proteins; MDS1 and EVI1 Complex Locus Protein; Proto-Oncogenes; Transcription Factors; Leukemia, Myeloid, Acute; Carcinogenesis; Transcriptional Regulator ERG
PubMed: 36095844
DOI: 10.1182/blood.2022016592 -
Nature Reviews. Cancer Dec 2018The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are... (Review)
Review
The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but also the factors influencing this event, which has implications for cancer prevention. To this end, we suggest that there is a narrow window or 'sweet spot' by which oncogenic RAS signalling can promote tumour initiation in normal cells. As a consequence, RAS mutation patterns in each normal cell are a product of the specific RAS isoform mutated, as well as the position of the mutation and type of substitution to achieve an ideal level of signalling.
Topics: Animals; Cell Transformation, Neoplastic; GTP Phosphohydrolases; Genes, ras; Humans; Membrane Proteins; Mice; Models, Genetic; Mutagenesis; Mutation; Neoplasms; Protein Isoforms; Proto-Oncogene Proteins p21(ras); Signal Transduction
PubMed: 30420765
DOI: 10.1038/s41568-018-0076-6 -
Molecular Cancer May 2023Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse,...
BACKGROUND
Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment.
METHODS
Candidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models.
RESULTS
We reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also.
CONCLUSION
We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.
Topics: Animals; Humans; Infant; Mice; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, myc; N-Myc Proto-Oncogene Protein; Neoplasm Recurrence, Local; Neuroblastoma
PubMed: 37246217
DOI: 10.1186/s12943-023-01792-0 -
Radiology and Oncology Sep 2019Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have... (Review)
Review
Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Genes, erbB-2; Genes, ras; Genetic Markers; Humans; Ipilimumab; Male; Microsatellite Instability; Mutation; Panitumumab; Prognosis; Proto-Oncogene Proteins B-raf; Sex Factors; Trastuzumab
PubMed: 31553708
DOI: 10.2478/raon-2019-0033