Resumen de Role of YES1 as an oncogenic driver and immunotherapy modulator in lung cancer
In this thesis we have made contributions about the role of the non-receptor tyrosine kinase YES1 in lung cancer. YES1 is a non-receptor tyrosine kinase that belongs to the SRC family kinases. Previous works had shown the prognostic and biological role of YES1 in several solid tumors. Here we showed that dasatinib-mediated YES1 inhibition modulated the tumor microenvironment (TME) in NSCLC by decreasing tumor immunosuppression. Combination of dasatinib with anti-PD-1 synergized causing tumor regressions by hampering the proliferation of Tregs and blocking the conversion of CD4 T cells into Tregs. On the other hand, we have found that YES1 expression constitutes an oncogenic dependency and an independent predictor of poor prognosis in SCLC, and that its pharmacological inhibition could represent a promising targeted therapy for a subset of SCLC patients. Furthermore, we have identified YES1 as a potential non-invasive biomarker in plasma from lung cancer patients. We have found that YES1 is released in exosomes in levels that matched their respective tumors. Moreover, exosomal YES1 levels are increased in both NSCLC and SCLC patients, which suggests that YES1 could be used as a liquid biopsy biomarker in lung cancer. Lastly, we have studied novel therapeutic strategies based on the pharmacological inhibition of YES1 in combination with immunotherapy to increase the sensitivity of SCLC to immune checkpoint inhibitors in preclinical models.
