Abstract
Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14-mutant NSCLC. Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS). A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14-mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses. On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.
Highlights
MET exon 14 alterations occur in approximately 3% of non–small cell lung cancers (NSCLCs) and predict for response to treatment with MET tyrosine kinase inhibitors (TKI; refs. 1, 2)
In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses
Type I MET inhibitors are further subclassified as type Ia when the drug interacts with the solvent front G1163 residue, and type Ib when drug binding to the kinase domain is independent from this interaction
Summary
MET exon 14 alterations occur in approximately 3% of non–small cell lung cancers (NSCLCs) and predict for response to treatment with MET tyrosine kinase inhibitors (TKI; refs. 1, 2). MET exon 14 alterations occur in approximately 3% of non–small cell lung cancers (NSCLCs) and predict for response to treatment with MET tyrosine kinase inhibitors Type I MET TKIs, such as crizotinib, capmatinib, tepotinib, and savolitinib, bind to MET in its catalytically active conformation where the aspartic acid-phenylalanine-glycine (DFG) motif projects into the ATP-binding site Type II MET TKIs such as cabozantinib, merestinib, and glesatinib bind to MET in its inactive DFG-out conformation [8,9,10]. Type I MET inhibitors are further subclassified as type Ia (crizotinib) when the drug interacts with the solvent front G1163 residue, and type Ib (capmatinib, tepotinib, and savolitinib) when drug binding to the kinase domain is independent from this interaction. Reports indicate that response rates with type I MET TKIs range from 32% to 55%, and the median progression-free survival (PFS) with these drugs varies between 5 and 12 months, and is limited by the invariable emergence of acquired resistance to these therapies [4, 5, 11,12,13]
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