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

## TL;DR

The study reveals how KRAS forms a weaker complex with SHOC2 and PP1C compared to MRAS, and suggests that targeting both complexes could help treat RAS-driven cancers.

## Contribution

The study provides structural insights into KRAS complex formation and proposes a strategy for dual inhibition to overcome cancer resistance.

## Key findings

- KRAS forms a lower-affinity SHOC2–KRAS–PP1C complex with fewer contacts than MRAS.
- RAS inhibitors block SKP assembly more effectively than preformed complexes.
- A MRAS mutant can bind MRTX1133, suggesting dual targeting of SKP and SMP complexes is feasible.

## Abstract

RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2–RAS–PP1C complex. MRAS forms a high-affinity SHOC2–MRAS–PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2–KRAS–PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2–RAS–PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.

RAS-driven cancers depend on SHOC2–PP1C. Here, the authors reveal that KRAS forms a low-affinity SHOC2–PP1C complex with fewer contacts than MRAS and show that dual inhibition of KRAS- and MRAS-dependent assemblies strengthens SHOC2 suppression and may overcome resistance.