SOS2 Is a Tractable Therapeutic Target to Limit Therapeutic Resistance in Non-Small Cell Lung Cancer

Our objective is to characterize SOS2 as a bona fide therapeutic target whose inhibition will limit therapeutic resistance in EGFR- and KRAS-mutated NSCLC. We hypothesize that SOS2 deletion reduces RTK-stimulated PI3K/AKT signaling to limit therapeutic resistance in EGFR- and KRAS-mutated NSCLCs. In year 1 of the proposal, we found that SOS2 deletion significantly reduces the development of osimertinib resistance in EGFR-mutated NSCLC cells, whereas SOS1 inhibition shows strong synergy with osimertinib in initial cell killing after initial treatment. Further, we found that SOS2 deletion reduces transforming (3D) growth of EGFR-mutated NSCLC cells at limiting serum concentrations. In KRAS-mutated NSCLC cells, we found that SOS2 deletion reduces transforming (3D) growth and synergizes with MEK inhibitors to limit cell survival. We have also published two primary research articles and one review based on these data.