Abstract A048: Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors

Abstract RAF activation is a critical step in MAPK signaling and requires both RAS engagement and dephosphorylation of a conserved phosphoserine by the SHOC2–RAS–PP1C complex. MRAS forms a high-affinity SHOC2–MRAS–PP1C (SMP) assembly, whereas canonical RAS isoforms (KRAS, HRAS, NRAS) create analogous complexes with lower affinity. Despite this, tumors driven by oncogenic KRAS, HRAS, or NRAS remain highly dependent on SHOC2, indicating that these weaker assemblies are functionally relevant for tumorigenesis. To investigate how canonical RAS proteins assemble into lower-affinity ternary complexes, we determined the cryo-EM structure of the SHOC2–KRAS–PP1C (SKP) complex, stabilized by Noonan syndrome-associated mutations. The SKP complex resembles the SMP architecture but engages fewer contacts and buries less surface area due to the absence of MRAS-specific structural elements that enhance stability. RAS inhibitors MRTX1133 and RMC-6236 reshape Switch-I/II regions, preventing SKP assembly more efficiently than they disrupt preformed complexes, while leaving SMP formation unaffected because they do not target MRAS. Given that MRAS is upregulated in KRAS inhibitor resistance, we characterize an MRAS variant that binds MRTX1133; although capable of forming SMP, its assembly is blocked by the inhibitor, highlighting the potential for dual targeting of SKP and SMP complexes. Collectively, these results reveal isoform-specific determinants of SHOC2–RAS–PP1C formation and provide a rationale for simultaneously inhibiting both SKP and SMP to counter resistance in RAS-driven cancers. Citation Format: Daniel A. Bonsor, Lorenzo I. Finci, Jacob R. Potter, Lucy C. Young, Vanessa E. Wall, Ruby Goldstein de Salazar, Katie R. Geis, Tyler Stephens, Joseph Finney, Dwight V. Nissley, Frank McCormick, Dhirendra K. Simanshu. Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A048.