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JAMA Otolaryngology-- Head & Neck... Sep 2023
Topics: Humans; Genomics; Thyroid Neoplasms; Proto-Oncogene Proteins c-ret
PubMed: 37410473
DOI: 10.1001/jamaoto.2023.1577 -
Journal of Hepatology Feb 2024There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic...
BACKGROUND & AIMS
There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA).
METHODS
A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro.
RESULTS
On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance.
CONCLUSIONS
These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.
CLINICAL TRIAL NUMBER
NCT02052778.
IMPACT AND IMPLICATIONS
We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.
Topics: Animals; Humans; Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Cholangiocarcinoma; Mutation; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Protein Kinase Inhibitors; Receptor, Fibroblast Growth Factor, Type 2
PubMed: 37972659
DOI: 10.1016/j.jhep.2023.10.041 -
The American Journal of Pathology Sep 2023The atypical protein kinase/ATPase RIO kinase (RIOK)-1 is involved in pre-40S ribosomal subunit production, cell-cycle progression, and protein arginine...
The atypical protein kinase/ATPase RIO kinase (RIOK)-1 is involved in pre-40S ribosomal subunit production, cell-cycle progression, and protein arginine N-methyltransferase 5 methylosome substrate recruitment. RIOK1 overexpression is a characteristic of several malignancies and is correlated with cancer stage, therapy resistance, poor patient survival, and other prognostic factors. However, its role in prostate cancer (PCa) is unknown. In this study, the expression, regulation, and therapeutic potential of RIOK1 in PCa were examined. RIOK1 mRNA and protein expression were elevated in PCa tissue samples and correlated with proliferative and protein homeostasis-related pathways. RIOK1 was identified as a downstream target gene of the c-myc/E2F transcription factors. Proliferation of PCa cells was significantly reduced with RIOK1 knockdown and overexpression of the dominant-negative RIOK1-D324A mutant. Biochemical inhibition of RIOK1 with toyocamycin led to strong antiproliferative effects in androgen receptor-negative and -positive PCa cell lines with EC values of 3.5 to 8.8 nmol/L. Rapid decreases in RIOK1 protein expression and total rRNA content, and a shift in the 28S/18S rRNA ratio, were found with toyocamycin treatment. Apoptosis was induced with toyocamycin treatment at a level similar to that with the chemotherapeutic drug docetaxel used in clinical practice. In summary, the current study indicates that RIOK1 is a part of the MYC oncogene network, and as such, could be considered for future treatment of patients with PCa.
Topics: Male; Humans; Genes, myc; Protein Kinases; Adenosine Triphosphatases; Toyocamycin; Cell Proliferation; Prostatic Neoplasms; E2F Transcription Factors; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 37301535
DOI: 10.1016/j.ajpath.2023.05.013 -
Journal of Advanced Research Dec 2023Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure....
BACKGROUND
Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure. We aimed to uncover MYC-associated molecular targets to provide new strategies for LIHC treatment.
METHODS
LIHC transcriptome datasets and clinical information were obtained from The Cancer Genome Atlas. A series of bioinformatics analyses were performed for 370 patients who were stratified based on the median MYC expression level (high-MYC group and low-MYC group). Correlation analysis was performed to determine relationships between the expression of key MYC-associated genes and prognosis, DNA promotor methylation, and immune cell infiltration. Gene ontology and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analyses were performed to elucidate the functions of these genes in LIHC. Their expression and functions in LIHC were further verified using transgenic mice overexpressing c-Myc under control of the hepatocyte-specific promoter (Alb-Cre).
RESULTS
AURKB, CCNB2, and CDKN3 were overexpressed in LIHC patients with high MYC expression and were associated with poor prognosis. Upregulation of these 3 genes was significantly correlated with hypomethylated promoter status, advanced T stage, metastasis, and immune cell infiltration in LIHC patients. Functional enrichment analyses indicated that these genes participate in the "p53 signaling pathway" and "cell cycle". Furthermore, RT-PCR and IHC analysis revealed that their mRNA and protein expression levels were upregulated in an Alb-Cre;cMYC mouse model. Drugs that target these 3 MYC-related genes were identified.
CONCLUSION
Taken together, our results identify biomarkers of potential utility for managing liver cancer therapy owing to their significance in tumorigenesis, proliferation, and tumor immunity.
Topics: Animals; Mice; Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Genes, myc; Genes, cdc
PubMed: 36716957
DOI: 10.1016/j.jare.2023.01.010 -
Cancer Biology & Medicine Jun 2024Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs,... (Review)
Review
Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2 (ERBB2), B-Raf proto-oncogene, serine/threonine kinase (BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase (ALK/ROS1), neurotrophic receptor tyrosine kinases (NTRKs), ret proto-oncogene (RET), fibroblast growth factor receptor 2 (FGFR2), and epidermal growth factor receptor (EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations.
Topics: Humans; Colorectal Neoplasms; Proto-Oncogene Mas; Genetic Variation; Mutation; Proto-Oncogene Proteins c-ret; Molecular Targeted Therapy; Proto-Oncogene Proteins B-raf; Precision Medicine; Biomarkers, Tumor; Protein-Tyrosine Kinases; Proto-Oncogene Proteins
PubMed: 38940668
DOI: 10.20892/j.issn.2095-3941.2024.0026 -
Life Sciences Mar 2024RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that...
AIMS
RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that regulates heart failure. This study aims to unravel a new biological function of RBM10 phosphorylation by proto-oncogene cSrc that enables anti-hypertrophy gene program and controls cardiac hypertrophy.
MATERIALS AND METHODS
We employ in vitro and in vivo approaches to characterise RBM10 phosphorylation at three-tyrosine residues (Y81, Y500, and Y971) by cSrc and target mRNA regulation. We also use isoproterenol induced rat heart and cellular hypertrophy model to determine role of cSrc-mediated RBM10 phosphorylation.
KEY FINDINGS
We show that RBM10 phosphorylation is induced in cellular and animal heart model of cardiac hypertrophy and regulates target mRNA expression and 3'-end formation. Inhibition of cSrc kinase or mutation of the three-tyrosine phosphorylation sites to phenylalanine accentuates myocyte hypertrophy, and results in advancement and an early attainment of hypertrophy in the heart. RBM10 is down regulated in the hypertrophic myocyte and that its re-expression reverses cellular and molecular changes in the myocyte. However, in the absence of phosphorylation (cSrc inhibition or phospho-deficient mutation), restoration of endogenous RBM10 level in the hypertrophic heart or ectopic re-expression in vitro failed to reverse cardiomyocyte hypertrophy. Mechanistically, loss of RBM10 phosphorylation inhibits nuclear localisation and interaction with Star-PAP compromising anti-hypertrophy gene expression.
SIGNIFICANCE
Our study establishes that cSrc-mediated RBM10 phosphorylation arbitrates anti-hypertrophy gene program. We also report a new functional regulation of RBM10 by phosphorylation that is poised to control heart failure.
Topics: Rats; Animals; Phosphorylation; Cardiomegaly; Heart Failure; Proto-Oncogenes; RNA, Messenger; Tyrosine; Myocytes, Cardiac
PubMed: 38309577
DOI: 10.1016/j.lfs.2024.122482 -
Biology Direct Oct 2023Bcl-B is a poorly understood protein of the Bcl-2 family that is highly expressed in many healthy tissues and tumor types. Bcl-B is considered an antiapoptotic protein,... (Review)
Review
Bcl-B is a poorly understood protein of the Bcl-2 family that is highly expressed in many healthy tissues and tumor types. Bcl-B is considered an antiapoptotic protein, but many reports have revealed its contradictory roles in different cancer types. In this mini-review, we elucidate the functions of Bcl-B in normal conditions and various pathologies, its regulation of programmed cell death, its oncogene/oncosuppressor activity in tumorigenesis, its impact on drug-acquired resistance, and possible approaches to inhibit Bcl-B.
Topics: Humans; Proto-Oncogene Proteins c-bcl-2; Apoptosis; Neoplasms
PubMed: 37899453
DOI: 10.1186/s13062-023-00431-4 -
The Treatment of a New Entity in Advanced Non-small Cell Lung Cancer: MET Exon 14 Skipping Mutation.Current Medicinal Chemistry 2024MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all... (Review)
Review
BACKGROUND
MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all mutations in advanced lung adenocarcinomas. While until 2020 no specific treatment was available for this subset of patients, as of today, three MET Tyrosine Kinase Inhibitors (TKIs) are currently approved in this setting, namely capmatinib, tepotinib and savolitinib.
OBJECTIVE
This article aims to provide an extensive overview of the current therapeutic standard of care for exon 14 skipped advanced Non-small Cell Lung Cancer (NSCLC) patients, alongside with mentions of the main future challenges and opportunities.
CONCLUSION
FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.
Topics: Humans; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Exons; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met
PubMed: 37534484
DOI: 10.2174/0929867331666230803094432 -
Postepy Biochemii Sep 2023Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the...
Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the BRAF gene. This mutation causes constitutive activation of the MAPK/ERK signaling pathway, significantly contributing to the process of carcinogenesis. We discuss the drug design process on the example of a specific BRAF V600E inhibitor, vemurafenib. We begin with the most commonly used drug design methods. The second part of the article focuses on vemurafenib. We analyze the invention of this BRAF V600E inhibitor and its analogue as well as the course of three stages of clinical trials. Then we provide information about other popular drugs for malignant melanoma, i.e. dacarbazine, ipilimumab and dabrafenib, and about the advantages of therapy with the simultaneous use of two inhibitors. Finally, we briefly discuss the role of artificial intelligence in the future of drug design.
Topics: Humans; Vemurafenib; Antineoplastic Agents; Proto-Oncogene Proteins B-raf; Artificial Intelligence; Indoles; Sulfonamides; Melanoma; Skin Neoplasms; Protein Kinase Inhibitors; Mutation; Drug Resistance, Neoplasm; Melanoma, Cutaneous Malignant
PubMed: 38019740
DOI: 10.18388/pb.2021_498 -
The Journal of Experimental Medicine Aug 2023Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for...
Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.
Topics: Animals; Mice; Antiviral Agents; COVID-19; Interferon Type I; SARS-CoV-2; Toll-Like Receptor 3; Genes, src
PubMed: 37158982
DOI: 10.1084/jem.20220727