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<p>MET-exon-14 skipping mutations (METΔex14) are oncogenic drivers in ~3–5% of lung cancer, which can be targeted with MET tyrosine kinase inhibitors (TKIs). The emergence of resistance limits long-term responses and is commonly mediated by secondary genomic alterations. We devised a preclinical strategy to study MET-TKI resistance using a dose-escalation approach on METΔex14-dependent cancer cells to generate MET-TKI-refractory isogenic counterparts. These cell lines were profiled for clinically relevant changes that we functionally evaluated for MET-TKI resistance. Targeted sequencing of resistant clones identified acquired mutations in <i>SPOP</i> and <i>MGA</i>, both antagonists of MYC activity. <i>SPOP</i>- and <i>MGA</i>-mutant clones exhibited higher MYC levels and transcriptomic signatures of MYC activation. Expression of MYC rescued tumor growth in the presence of TKI, while MYC depletion mimicked the cytotoxic effect of TKI treatment, indicating that MYC activity is coupled to MET signaling and MYC is required to mediate drug resistance. Analysis of clinical METΔex14-positive lung cancers revealed several cases where acquired MYC pathway alterations mediated resistance to MET-TKIs. These findings collectively converge on MYC as key in the progression of MET TKI-resistant cancers, and our in vitro data support the strategy of co-targeting MYC and MET to yield more prolonged responses in patients with METΔex14-positive lung cancer.</p>

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MYC contributes to targeted therapy resistance in lung cancers driven by MET exon 14-skipping alteration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Daniel Lu,
  • Sarah Okun,
  • Tom Zhang,
  • Andrea Gazzo,
  • Amy Kang,
  • Amy Nagelberg,
  • Justine L. M. Chow,
  • Haijie Liang,
  • Anmol Kustagi,
  • Christopher A. Febres-Aldana,
  • Marc Ladanyi,
  • Romel Somwar,
  • William W. Lockwood

摘要

MET-exon-14 skipping mutations (METΔex14) are oncogenic drivers in ~3–5% of lung cancer, which can be targeted with MET tyrosine kinase inhibitors (TKIs). The emergence of resistance limits long-term responses and is commonly mediated by secondary genomic alterations. We devised a preclinical strategy to study MET-TKI resistance using a dose-escalation approach on METΔex14-dependent cancer cells to generate MET-TKI-refractory isogenic counterparts. These cell lines were profiled for clinically relevant changes that we functionally evaluated for MET-TKI resistance. Targeted sequencing of resistant clones identified acquired mutations in SPOP and MGA, both antagonists of MYC activity. SPOP- and MGA-mutant clones exhibited higher MYC levels and transcriptomic signatures of MYC activation. Expression of MYC rescued tumor growth in the presence of TKI, while MYC depletion mimicked the cytotoxic effect of TKI treatment, indicating that MYC activity is coupled to MET signaling and MYC is required to mediate drug resistance. Analysis of clinical METΔex14-positive lung cancers revealed several cases where acquired MYC pathway alterations mediated resistance to MET-TKIs. These findings collectively converge on MYC as key in the progression of MET TKI-resistant cancers, and our in vitro data support the strategy of co-targeting MYC and MET to yield more prolonged responses in patients with METΔex14-positive lung cancer.