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

被引：15

作者：

Rosell, Rafael ^{[1
,2
,9
]}

Codony-Servat, Jordi ^{[3
]}

Gonzalez, Jessica ^{[1
]}

Santarpia, Mariacarmela ^{[4
]}

Jain, Anisha ^{[5
]}

Shivamallu, Chandan ^{[6
]}

Wang, Yu ^{[7
]}

Gimenez-Capitan, Ana ^{[3
]}

Molina-Vila, Miguel A. ^{[3
]}

Nilsson, Jonas ^{[8
]}

Gonzalez-Cao, Maria ^{[2
]}

机构：

[1] Germans Trias i Pujol Res Inst IGTP, Badalona, Spain

[2] Hosp Quiron Dexeus, IOR, Barcelona, Spain

[3] Hosp Quiron Dexeus, Pangaea Oncol, Barcelona, Spain

[4] Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Messina, Italy

[5] JSS Acad Higher Educ & Res, Dept Microbiol, Mysuru, India

[6] JSS Acad Higher Educ & Res, Dept Biotechnol & Bioinformat, Mysuru, Karnataka, India

[7] Genfleet Therapeut, Shanghai, Peoples R China

[8] Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden

[9] Germans Trias i Pujol Hlth Sci Inst & Hosp IGTP, Lab Mol Biol, Cami Escoles S-N, Barcelona 08916, Spain

来源：

CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY | 2024年 / 195卷

关键词：

NSCLC; KRAS G12C; SHOC2; MRAS; AQP5; STK11/LKB1; HUWE1; RGS3; VCP; Immunotherapy; UNPHOSPHORYLATED STAT3; AAA-ATPASE; C-RAF; INHIBITION; ADENOCARCINOMA; RESISTANCE; MUTATIONS; MECHANISM; STK11; PROGRESSION;

D O I：

10.1016/j.critrevonc.2023.104228

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：19

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