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 family kinases (SFKs), can be found in a significant subset of lung cancer patients. OBJECTIVES to evaluate YES1 genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. METHODS functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts (PDX). The efficacy of pharmacological and genetic (CRISPR/Cas9) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival and invasion, were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. MEASUREMENTS AND MAIN RESULTS we demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR signaling. Interestingly, cell lines and PDX models with YES1 gene amplifications presented a high sensitivity to dasatinib, a SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in lung cancer patients. 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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