LAUSR

Activating RAS mutations constitute the majority of recurrent mutations found in MAPK-driven human tumors. However, RAS mutants have long been considered undruggable, and therefore efforts have been predominantly focused on targeting downstream MAPK signaling. We and others have shown that, MAPK inhibition using MEK inhibitors (MEKi) have limited effectiveness in such tumors due to adaptive resistance. A major mechanism of adaptive resistance involves relief of negative feedback that promotes reactivation of RTK signaling, which in turn activates RAS and results in MAPK rebound. The recent development of direct (i.e. RAS(G12C)) and indirect (i.e. SHP2i, SOSi) inhibitors of RAS have uncovered the dependence of activity of RAS(G12C) and of other RAS mutants on upstream signaling. We and others have previously characterized sensitivity of various RAS mutants in cancer to either SHP2 inhibition (SHP2i), or to combination of SHP2i with MEKi, but a systematic characterization of most RAS mutants commonly expressed in cancer has been lacking. In this study, by combining biochemical and chemical genetic approaches we identified two classes of RAS-mutants, based on their degree of dependency on RTK/SHP2 signaling and adaptation to MEK inhibition. One class of RAS mutants, including most RASQ61X, show complete independence from RTK/SHP2 signaling and are fully resistant to either SHP2i alone or in combination with MEKi. The other class includes the majority of RAS mutants and is characterized by relative resistance to SHP2i, or the combination of SHP2i plus MEKi, compared to cells expressing wild-type RAS, including normal cells. Early clinical data using single agent SHP2i or combinations of SHP2i with MEKi for the treatment of patients with RAS-mutant tumors suggested modest activity as well as dose-limiting on-target (i.e. MAPK pathway related) toxicities. Our findings predict that achieving an acceptable therapeutic index by either approach for treatment of RAS-mutant tumors will be challenging, and they support instead SHP2i-based therapeutic efforts in patients with MAPK-driven tumors expressing wild-type RAS, or in combination with RAS-mutant selective inhibitors. Collectively this work provides a framework for the design of SHP2i-based treatments for patients with MAPK-driven tumors, the majority of which currently have no effective targeted therapeutic options. Citation Format: Beau Baars, Christos Adamopoulos, Ana Orive-Ramos, Stuart A. Aaronson, Poulikos I. Poulikakos. RTK/SHP2 dependency and feedback adaptation to MEK inhibition defines sensitivity of RAS-mutant proteins to SHP2 inhibitor-based therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3413.