Overcoming MET-mediated resistance in oncogene-driven NSCLC

Nadine Reischmann; Carolin Schmelas; Miguel Ángel Molina-Vila; Núria Jordana-Ariza; Daniel Kuntze; Silvia García-Roman; Manon A Simard; Doreen Musch; Christina Esdar; Joachim Albers; Niki Karachaliou

doi:10.1016/j.isci.2023.107006

Overcoming MET-mediated resistance in oncogene-driven NSCLC

iScience. 2023 May 29;26(7):107006. doi: 10.1016/j.isci.2023.107006. eCollection 2023 Jul 21.

Affiliations

¹ The Healthcare Business of Merck KGaA, Darmstadt, Germany.
² Pangaea Oncology, Hospital Universitario Quiron-Dexeus, Barcelona, Spain.

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 EGFR^ex19del-, KRAS^G12C-, HER2^ex20ins-, 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.