2. Academic Validation
  3. KRAS G12C-mutant driven non-small cell lung cancer (NSCLC)

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

  • Crit Rev Oncol Hematol. 2024 Mar:195:104228. doi: 10.1016/j.critrevonc.2023.104228.
Rafael Rosell 1,  Jordi Codony-Servat 2,  Jessica González 3,  Mariacarmela Santarpia 4,  Anisha Jain 5,  Chandan Shivamallu 6,  Yu Wang 7,  Ana Giménez-Capitán 2,  Miguel A Molina-Vila 2,  Jonas Nilsson 8,  María González-Cao 9
Affiliations

Affiliations

  • 1 Germans Trias i Pujol Research Institute, Badalona (IGTP), Spain; IOR, Hospital Quiron-Dexeus, Barcelona, Spain. Electronic address: rrosell@iconcologia.net.
  • 2 Pangaea Oncology, Hospital Quiron-Dexeus, Barcelona, Spain.
  • 3 Germans Trias i Pujol Research Institute, Badalona (IGTP), Spain.
  • 4 Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Italy.
  • 5 Department of Microbiology, JSS Academy of Higher Education & Research, Mysuru, India.
  • 6 Department of Biotechnology & Bioinformatics, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
  • 7 Genfleet Therapeutics, Shanghai, China.
  • 8 Department Radiation Sciences, Oncology, Umeå University, Sweden.
  • 9 IOR, Hospital Quiron-Dexeus, Barcelona, Spain.
PMID: 38072173 DOI: 10.1016/j.critrevonc.2023.104228
Abstract

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.

Keywords

AQP5; HUWE1; Immunotherapy; KRAS G12C; MRAS; NSCLC; RGS3; SHOC2; STK11/LKB1; VCP.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-152848
    KRAS抑制剂
    Ras
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