KRAS G12C-mutant driven non-small cell lung cancer (NSCLC)

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 treat...

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Published in:	Critical reviews in oncology/hematology 2024-03, Vol.195, p.104228-104228, Article 104228
Main Authors:	Rosell, Rafael, Codony-Servat, Jordi, González, Jessica, Santarpia, Mariacarmela, Jain, Anisha, Shivamallu, Chandan, Wang, Yu, Giménez-Capitán, Ana, Molina-Vila, Miguel A., Nilsson, Jonas, González-Cao, María
Format:	Article
Language:	eng
Subjects:	AQP5 Carboplatin Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Humans HUWE1 Immunotherapy Intracellular Signaling Peptides and Proteins KRAS G12C Lung Neoplasms - drug therapy Lung Neoplasms - genetics MRAS Mutation NSCLC Paclitaxel Proto-Oncogene Proteins p21(ras) - genetics RGS3 SHOC2 STK11/LKB1 Tumor Suppressor Proteins - genetics Ubiquitin-Protein Ligases VCP
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Summary:	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. •KRAS G12C mutations in NSCLC respond partially to KRAS inhibitors.•Factors implicated in early adaptive resistance: activation of receptor tyrosine kinases (EGFR, MET, ligands).•Activation of MRAS:SHOC2:PP1C trimeric complex causes early resistance to KRAS inhibitors.•Reactivation of MRAS complex is regulated by valosin containing protein (VCP).
ISSN:	1040-8428 1879-0461 1879-0461