2024 World Conference on Lung Cancer (WCLC) - Posters-P3.12C.02 MET Fusions in NSCLC: Prevalence, Oncogenicity, and Resistance Mechanism

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This document outlines a study on MET fusions in non-small cell lung cancer (NSCLC), focusing on their prevalence, oncogenic potential, and mechanisms of resistance. Researchers found MET fusions in 0.12% of NSCLC cases (42/33,927), highlighting them as a rare but significant oncogenic driver. The most common fusion partner was ST7 (19%), followed by HLA-DRB1 (14%) and KIF5B (10%). <br /><br />MET fusions often coexist with other oncogenic alterations in 33% of cases, including EGFR and KRAS mutations, and are associated with MET amplification in 35% of cases. The median age of patients was 66 years, with adenocarcinoma as the most common histology. <br /><br />The study examined the HLA-DRB1::MET fusion, evaluating its role as an oncogenic driver and a resistance mechanism to targeted therapies. In one clinical case, the MET fusion showed responsiveness to MET tyrosine kinase inhibitors (TKIs), but developed resistance upon acquiring a D1228V mutation in the MET kinase domain. This resistance was studied through in vitro models, which confirmed the oncogenicity of the HLA-DRB1::MET fusion and demonstrated its resistance to type I MET TKIs in cells.<br /><br />The research also explored the dimerization of HLA-DRB1::MET and its role in activating downstream signaling pathways through the recruitment of adapter molecules like SOS1. Additionally, it was found that HLA-DRB1::MET can confer resistance to EGFR TKIs in EGFR-mutant cells, a resistance that can be overcome by adding MET TKIs.<br /><br />These findings suggest MET fusions as potential targets for personalized cancer therapy, emphasizing the importance of comprehensive molecular profiling in managing NSCLC. The study proposes combinatorial treatment strategies to counter resistance in oncogene-driven NSCLC with MET fusions.

Asset Subtitle

Seshiru Nakazawa

Meta Tag

Speaker Seshiru Nakazawa

Topic Metastatic NSCLC – Targeted Therapy

Keywords

MET fusions

non-small cell lung cancer

NSCLC

oncogenic potential

resistance mechanisms

HLA-DRB1::MET

tyrosine kinase inhibitors

EGFR mutations

personalized cancer therapy

molecular profiling