Articles: proto-oncogene-proteins-c-yes.
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Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. ⋯ Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.
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Am. J. Respir. Crit. Care Med. · Oct 2019
YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib.
Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. ⋯ Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2018
YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics.
In ∼30% of patients with EGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. ⋯ None of 136 postinhibitor samples had detectable amplification of other Src family kinases (SRC and FYN). YES1 amplification was also found in 2 of 17 samples from ALK fusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification of YES1 as a recurrent and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.
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World journal of urology · Mar 2018
MiR-199a suppresses prostate cancer paclitaxel resistance by targeting YES1.
Prostate cancer chemoresistance is a major contributor to the poor survival of patients. MicroRNAs (miRNAs) play an important role in regulating cancer resistance. Here we aim to explore the role and mechanism of miR-199a in regulating prostate cancer resistance. ⋯ The downregulation of miR-199a contributes to PTX resistance in prostate cancer. YES1 mediates the regulation of miR-199a in prostate cancer PTX resistance. This miR-199a replacement therapy has potential to overcome PTX resistance.