LAUSR

Background: Mutations in the KRAS gene are present in approximately 25% of lung adenocarcinoma cases and are associated with poor prognosis and resistance to anti-EGFR therapy. Although sorafenib has shown considerable promise in the treatment of KRAS mutant NSCLC, resistance to the treatment eventually occurs. We have previously reported that acquired sorafenib resistance in KRAS-mutant A549 xenografts involves the compensatory activation of focal adhesion kinase (FAK) and Src, while inhibition of Src alone is insufficient to overcome the resistance. Objectives: Our aim in this study was to demonstrate simultaneous blockade of FAK and Src activation as a potential strategy to enhance the antitumor activity of sorafenib in KRAS mutant NSCLC. Methods: The cytotoxicity of sorafenib and dasatinib used as a single agent or in combination was initially determined in human NSCLC cells (A549, H358 and H1915 cells), with either non-targeting control shRNA or FAK shRNA knockdown. Based on the initial findings, the cytotoxicity of sorafenib, dasatinib and FAK inhibitor 14 used as a single agent or in combination was examined in A549 cells. Western blot analysis was conducted to reveal possible mechanisms underlying the improved therapeutic effect. Results: Among the three selected human NSCLC cell lines, H358 (with G12C KRAS mutation) was the most sensitive and H1915 (with wild-type KRAS) was the most resistant to treatment with dasatinib and sorafenib alone or in combination. In A549 cells with G12S KRAS mutation, FAK knockdown significantly increased the sensitivity of cells to dasatinib treatment (P Conclusions: Results of our in vitro study warrants further evaluation of the triple combination therapy with sorafenib, dasatinib and an effective FAK inhibitor in the treatment of NSCLC with G12S KRAS mutation. Citation Format: Qingyu Stephanie Zhou, Mitchell West. Blockade of FAK and Src activation enhances antitumor activity of sorafenib in non-small cell lung carcinomas harboring G12S KRAS mutation [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 4889.