Synergistic Inhibition of Drug Resistant KRAS Mutant Non-Small Cell Lung Cancer by Co-Targeting AXL and SRC

Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic pathways through the AXL-SRC-Akt axis. In this study, we identify AXL as the bypass resistant gene and investigate its role with KRAS and SRC activity. Methods: In this study, we use Dasatinib and SGI-7079 to co-inhibit SRC and AXL respectively. In vitro studies were conducted using four cell lines, and AXL suppression was achieved using siRNA and in CRISPR-Cas9 mediated knockout models. Subsequently, we studied gene-protein expression analysis using Western blot, apoptotic markers using a cytochrome release assay and cytotoxicity using an MTT assay. A549 xenografts were studied for in vivo validation of our proposed hypothesis. Results: The results suggest that dual inhibition of AXL and SRC significantly reversed this resistance, both in in vivo and in vitro studies. Conclusions: Co-inhibition of AXL and SRC synergistically reduced KRAS activity and induced apoptosis in NSCLC.