Lung cancer is the leading cause of cancer-related death worldwide; adenocarcinoma is the most common subtype of lung cancer. Oncogenic driver mutations in the RTK/RAS pathway occur in 75-90% of lung adenocarcinoma (LUAD). Receptor Tyrosine Kinase (RTK) and RAS pathway-targeted therapies have substantially improved outcomes in LUAD. However, in most cases both intrinsic and acquired resistance to these agents limits their long-term effectiveness. Resistance to osimertinib in EGFR-mutated tumors, KRASG12C inhibitors in KRASG12C-mutated tumors, or the MEK inhibitor trametinib in KRAS-mutated and NF1-LOF tumors most often develops via activation of multiple RTKs, often within the same tumor. These data suggest that combating therapeutic resistance via individual RTK inhibitors will be ineffective. In contrast, we hypothesize that broad inhibition of RTK signaling via a common downstream signaling node has the potential to enhance the efficacy of and delay resistance to targeted therapies in a majority of LUADs.

To test this hypothesis, we built an experimental framework that models the evolution of cancer cells to therapeutic pressure in situ. Using this framework, we assess for therapeutic combinations that (i) enhance therapeutic efficacy to overcome intrinsic/adaptive resistance, (ii) limit the survival of drug-tolerant persister (DTP) cells capable of driving acquired resistance, and (iii) delay the onset of and/or block the development of resistant cultures.

Using this framework we show that proximal RTK signaling intermediates SHP2, SOS1, and SOS2 are therapeutic targets whose inhibition both enhance the efficacy of and delay resistance to RTK/RAS pathway-targeted therapies by targeting DTPs in EGFR-mutated, KRASG12-mutated, and NF1-LOF LUAD cells. We further show that the effectiveness of co-targeting proximal RTK signaling showed genotype-specificity; SOS1 inhibitors did not synergize with or prevent resistance to MEK inhibitors in KRASQ61-mutated cells or cells harboring PIK3CA co-mutations. Finally, we show that SOS1i can re-sensitize G12Ci and EGFRi DTPs to oncogene-targeted therapies, and combined EGFRi+SOS1i treatment inhibited EGFR-mutated tumor growth in vivo to a greater extent than EGFRi alone.

Our data present a framework for rapidly evaluating and selecting optimal combinations therapies prior to moving into extensive longitudinal pre-clinical animal studies. Our data further show that targeting proximal RTK signaling in combination therapy using a SOS1 inhibitor is a potential strategy to prolong the effectiveness of oncogene-targeted therapies for a majority of LUAD patients.