Abstract B007: Proximal RTK signaling regulates tumor initiating cell survival and therapeutic responsiveness in EGFR- and KRAS-mutated lung adenocarcinoma
Authors: Daley Brianna , Kortum Rob 
Published: May 2023

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 LUAD. Oncogene-targeted therapies substantially improve outcomes in LUAD; however, recalcitrant tumors invariably emerge necessitating novel therapeutic approaches that either delay therapeutic resistance or treat resistant cancers to enhance patient outcomes. Resistance to oncogene-targeted therapies in LUAD is commonly due to RTK pathway reactivation. Resistance to osimertinib in EGFR-mutated tumors, KRASG12C inhibitors (sotorasib, adagrasib) in KRASG12C-mutated tumors, or MEK inhibitors (trametinib) in KRAS (non-G12C)-mutated tumors often develops via activation of multiple RTKs. The multiplicity of RTKs that can be activated to drive resistance suggests that individual RTK inhibitors will be ineffective alone, while broad inhibition of RTK signaling can enhance the efficacy of and delay resistance to targeted therapies in LUAD. Tumor initiating cells (TICs) are a functional subset of LUAD cells that exhibit self-renewal and are recalcitrant to oncogene-targeted therapies; it has been hypothesized that therapy-resistant TICs are the sanctuary population within the bulk tumor responsible for therapeutic resistance. Targeted ablation of TICs has the potential to enhance the efficacy of and delay resistance to targeted therapies in LUAD. We found that proximal RTK inhibition (SOS1-I and/or SOS2 KO) enhanced the killing effect of oncogene-targeted therapies under 3D culture conditions. SOS1 inhibition and/or SOS2 KO further delayed resistance to oncogenic targeted therapies in both EGFR- and KRASG12C-mutated cell lines. Since TICs are proposed as driving therapeutic resistance, these data suggested that SOS1/2 may regulate TIC survival. TICs can be functionally defined by their ability to proliferate in 3D culture from a single cell. Using this functional definition, we found that 72-h treatment with the G12C-Is adagrasib or sotorasib enriched for functional TICs 2-3 fold in multiple KRASG12C-mutated cell lines, suggesting that TICs could act as a sanctuary population of G12C-I resistant cells. We further isolated cells based on ALDH activity and found isolated ALDHhigh TICs are markedly recalcitrant to short-term G12C-I treatment. In both cases, we found that SOS1-I and/or SOS2 KO inhibited the recalcitrance of TICs to G12C inhibitors to synergistically inhibit TIC survival. These data suggest that SOS1 inhibition and/or SOS2 KO impedes the development of resistance to oncogenic targeted therapy by targeting TIC outgrowth.

Citation Format: Brianna Daley, Rob Kortum. Proximal RTK signaling regulates tumor initiating cell survival and therapeutic responsiveness in EGFR- and KRAS-mutated lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B007.