The three RAS genes are the most commonly mutated oncogenes in cancer and have long been considered an “undruggable” target. Alterations in KRAS occur at the highest frequency, with G12D, G12V, and G12C mutations being the most common. The recent development of novel covalent inhibitors selective for the KRASG12C mutation offers the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway in have been hampered by adaptive feedback, which drives pathway reactivation and resistance. We find evidence of rapid adaptive RAS-MAPK pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, including lung, colon, and pancreatic lines. Reactivation of the RAS-MAPK pathway correlates with activation of multiple upstream RTKs and subsequent increase of wild-type RAS activity. We find that co-inhibition of SHP2, a common node downstream of RTKs, or co-inhibition of individual RTKs such as EGFR or FGFR enhances the efficacy of KRASG12C inhibition both in vitro and in vivo by overcoming adaptive reactivation of the RAS-MAPK pathway. Notably, only the combination of KRASG12C and SHP2 inhibitor treatment displays tumor regressions in vivo in multiple models when compared to either inhibitor alone. We also see evidence that combining KRASG12C inhibitors with MEK or ERK inhibitors as an additional potential vertical inhibition strategy in KRASG12C models. We propose a vertical inhibition strategy anchored with KRASG12C inhibitors with either RTK or SHP2 inhibitors as a potential strategy for the treatment of KRASG12C mutant tumors.

Citation Format: Meagan B Ryan, Ferran Fece de la Cruz, Sarah Phat, David T Myers, Heather A Shahzade, Catriona B Hong, Ryan B Corcoran. Vertical inhibition overcomes adaptive resistance to KRASG12C inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A129. doi:10.1158/1535-7163.TARG-19-A129