Background: Capmatinib, a potent and selective mesenchymalepithelial transition factor (MET) inhibitor, is an effective treatment option for non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations or gene amplification. However, the mechanisms that confer resistance to capmatinib remain elusive. Here, we present a case of primary resistance to capmatinib in a MET-amplified NSCLC patient which was conferred by concurrent MYC amplification.
Case description: Capmatinib was administered as first-line treatment in an 82-year-old MET-amplified [gene copy number (GCN) 13.5] and MET overexpressed (immunohistochemical staining 3+/3, >50%) NSCLC patient. However, the tumor rapidly progressed and showed primary resistance to capmatinib. Next-generation target sequencing using rebiopsy tumor samples revealed MYC amplification. We also performed functional drug susceptibility testing using patient-derived cells (PDCs), which showed overexpression of MYC mRNA and resistance to capmatinib. Meanwhile, ICX-101, an investigational MYC inhibitor, successfully inhibited the growth of PDCs at a relatively low IC50 value. Also, a synergistic effect was shown when capmatinib treatment was followed by ICX-101.
Conclusions: Concurrent MYC amplification could potentially confer primary resistance to capmatinib in highly MET amplified NSCLC patients. Further clinical studies are warranted to corroborate these findings, and treatment with MYC inhibitors could be suggested as an alternative therapeutic strategy for this subset of patients.
Keywords: Capmatinib; MYC; case report; lung cancer; mesenchymal-epithelial transition factor (MET).
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