Abstract LB-084: Dasatinib reduces tumor growth in xenograft models derived from human lung tumors with YES1 overexpression

Introduction Lung cancer accounts for 13.2% of all new cancer cases and is the leading cause of cancer-related death worldwide. For a reduction of mortality rates, new personalized therapies are needed. The great challenge is to identify the alterations responsible for the tumor malignant phenotype which should be targeted by specific therapeutic strategies. The aim of our study is to evaluate the use of YES1 kinase amplification and overexpression as a companion biomarker to predict sensitivity to dasatinib using patient-derived xenograft models. Previous results Our previous experiments showed that downregulation of YES1 expression by specific siRNAs impairs cell proliferation and survival in lung cancer cell lines with amplification and high expression of YES1 (YES1High). Inhibition of YES1 in cell lines with normal copy number and low expression (YES1Low) had no effect on cell proliferation. Moreover, YES1 downregulation induced apoptosis and inhibited invasion only in YES1High cells, and YES1 overexpression promoted proliferation in lung cancer cell lines. Methods Eight patient-derived xenograft mouse models were used: two YES1High adenocarcinomas (ADC), two YES1Low ADC, two YES1High squamous cell carcinomas (SCC) and two YES1Low SCC. Small fragments of xenografted tumors (2-3 mm in diameter) were subcutaneously implanted into the right flank of 7-8-week-old BALB/c‐Rag2−/−‐IL2γc−/− immunodeficient mice. Mice were treated with dasatinib (60 mg/kg) or citric acid daily by oral gavage. Tumor volume was measured twice a week. Tumor volumes were calculated by the formula (LxW2)/2. Results In those tumors harboring YES1 amplification (YES1High), dasatinib significantly reduced tumor growth. This treatment induced tumor response in both ADC and SCC PDX models. On the contrary, in tumors with low expression of YES1, dasatinib did not affect tumor growth in ADC or SCC PDX models. Conclusions Dasatinib treatment significantly reduces tumor growth in YES1High PDX models but not in YES1Low models, providing support to our hypothesis that YES1 expression may be a useful companion biomarker for dasatinib as NSCLC treatment. Citation Format: Irati Garmendia, Cristina Bertolo, Irene Ferrer, Maria J Pajares, Daniel Ajona, Luis Paz-Ares, Ruben Pio, Luis M Montuenga, Jackeline Agorreta. Dasatinib reduces tumor growth in xenograft models derived from human lung tumors with YES1 overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-084.