Overcoming MET-mediated resistance in oncogene-driven NSCLC

  • iScience. 2023 May 29;26(7):107006. doi: 10.1016/j.isci.2023.107006.
Nadine Reischmann  1 ,  Carolin Schmelas  1 ,  Miguel Ángel Molina-Vila  2 ,  Núria Jordana-Ariza  2 ,  Daniel Kuntze  1 ,  Silvia García-Roman  2 ,  Manon A Simard  1 ,  Doreen Musch  1 ,  Christina Esdar  1 ,  Joachim Albers  1 ,  Niki Karachaliou  1
Affiliations
  • 1. The Healthcare Business of Merck KGaA, Darmstadt, Germany.
  • 2. Pangaea Oncology, Hospital Universitario Quiron-Dexeus, Barcelona, Spain.
PMID: 37534190 DOI: 10.1016/j.isci.2023.107006
Abstract

This study evaluates the efficacy of combining targeted therapies with MET or SHP2 inhibitors to overcome MET-mediated resistance in different NSCLC subtypes. A prevalence study was conducted for MET amplification and overexpression in samples from patients with NSCLC who relapsed on ALK, ROS1, or RET tyrosine kinase inhibitors. MET-mediated resistance was detected in 37.5% of tissue biopsies, which allow the detection of MET overexpression, compared to 7.4% of liquid biopsies. The development of drug resistance by MET overexpression was confirmed in EGFRex19del-, KRASG12C-, HER2ex20ins-, and TPM3-NTRK1-mutant cell lines. The combination of targeted therapy with MET or SHP2 inhibitors was found to overcome MET-mediated resistance in both in vitro and in vivo assays. This study highlights the importance of considering MET overexpression as a resistance driver to NSCLC targeted therapies to better identify patients who could potentially benefit from combination approaches with MET or SHP2 inhibitors.

Keywords
Cancer; Health sciences; Molecular physiology.
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