Available online 9 December 2023, 104228

KRAS G12C mutations in NSCLC respond partially to KRAS inhibitors

Signaling pathway rewiring identified as a key factor in early adaptive resistance. Activation of receptor tyrosine kinases (EGFR, MET, ligands) noted, particularly EGFR.

Activation of MRAS:SHOC2:PP1C trimeric complex causes early resistance to KRAS inhibitors

Reactivation of MRAS complex is regulated by valosin containing protein (VCP).

KRAS G12C mutations in non-small cell lung cancer (NSCLC) partially respond to KRAS G12C covalent inhibitors. However, early adaptive resistance occurs due to rewiring of signaling pathways, activating receptor tyrosine kinases, primarily EGFR, but also MET and ligands. Evidence indicates that treatment with KRAS G12C inhibitors (sotorasib) triggers the MRAS:SHOC2:PP1C trimeric complex. Activation of MRAS occurs from alterations in the Scribble and Hippo-dependent pathways, leading to YAP activation. Other mechanisms that involve STAT3 signaling are intertwined with the activation of MRAS. The high-resolution MRAS:SHOC2:PP1C crystallization structure allows in silico analysis for drug development. Activation of MRAS:SHOC2:PP1C is primarily Scribble-driven and downregulated by HUWE1. The reactivation of the MRAS complex is carried out by valosin containing protein (VCP). Exploring these pathways as therapeutic targets and their impact on different chemotherapeutic agents (carboplatin, paclitaxel) is crucial. Comutations in STK11/LKB1 often co-occur with KRAS G12C, jeopardizing the effect of immune checkpoint (anti-PD1/PDL1) inhibitors.

NSCLC

KRAS G12C

SHOC2

MRAS

AQP5

STK11/LKB1

HUWE1

RGS3

VCP

immunotherapy

© 2023 The Author(s). Published by Elsevier B.V.