KRAS G12C-mutant driven non-small cell lung cancer (NSCLC)
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Codony-Servat, Jordi (Hospital Quiron-Dexeus)
González Miranda, Jessica (Institut Germans Trias i Pujol)
Santarpia, Mariacarmela (Università degli Studi di Messina)
Jain, Anisha (JSS Academy of Higher Education & Research (Mysuru, Índia))
Shivamallu, Chandan (JSS Academy of Higher Education & Research (Mysuru, Índia))
Wang, Yu (Genfleet Therapeutics (Shanghai, Xina))
Giménez-Capitán, Ana (Hospital Quiron-Dexeus)
Molina Vila, Miguel Ángel (Hospital Quiron-Dexeus)
Nilsson, Jonas (Umeå University)
González-Cao, María (Hospital Quiron-Dexeus)
Universitat Autònoma de Barcelona

Data:	2024
Resum:	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.
Nota:	This work is in memory of the generous support provided by the late Julian Santamaría Valiño to the IOR Foundation.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article de revisió ; recerca ; Versió publicada
Publicat a:	Critical Reviews in Oncology/Hematology, Vol. 195 (march 2024) , p. 104228, ISSN 1879-0461

DOI: 10.1016/j.critrevonc.2023.104228

19 p, 9.4 MB

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