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<p>Lorlatinib, a third-generation ALK tyrosine kinase inhibitor (TKI), effectively targets most single ALK mutations in ALK-positive non-small cell lung cancer (NSCLC), while acquired resistance remains a major clinical challenge. In this study, we identified a novel ALK K1150dup mutation in a patient who progressed on first-line lorlatinib. Functional studies using EML4::ALK-dependent Ba/F3 cells demonstrated that ALK K1150dup confers resistance to lorlatinib and other ALK-TKIs including NVL-655 (neladalkib), with sustained ALK phosphorylation and downstream signaling. Importantly, multi-kinase inhibitor gilteritinib potently inhibited ALK phosphorylation and suppressed proliferation of ALK K1150dup-mutant cells. These findings reveal K1150dup as a previously unidentified mechanism of resistance to first-line lorlatinib, and highlight gilteritinib as a potential therapeutic option for patients harboring this mutation. Notably, they also challenge the prevailing assumption that first-line lorlatinib precludes the emergence of single on-target ALK resistance mutations.</p>

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The novel ALK K1150dup mutation mediates resistance to frontline lorlatinib and retains sensitivity to gilteritinib

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Mai Nagasaka,
  • Francesco Facchinetti,
  • Ludovic Bigot,
  • Floriane Brayé,
  • Matthew R. Groves,
  • Juvenal Yosa,
  • Anthonie van der Wekken,
  • Mihaela Aldea,
  • Benjamin Besse,
  • David Planchard,
  • Charles Naltet,
  • Ryohei Katayama,
  • Ken André Olaussen,
  • Yohann Loriot,
  • Luc Friboulet

摘要

Lorlatinib, a third-generation ALK tyrosine kinase inhibitor (TKI), effectively targets most single ALK mutations in ALK-positive non-small cell lung cancer (NSCLC), while acquired resistance remains a major clinical challenge. In this study, we identified a novel ALK K1150dup mutation in a patient who progressed on first-line lorlatinib. Functional studies using EML4::ALK-dependent Ba/F3 cells demonstrated that ALK K1150dup confers resistance to lorlatinib and other ALK-TKIs including NVL-655 (neladalkib), with sustained ALK phosphorylation and downstream signaling. Importantly, multi-kinase inhibitor gilteritinib potently inhibited ALK phosphorylation and suppressed proliferation of ALK K1150dup-mutant cells. These findings reveal K1150dup as a previously unidentified mechanism of resistance to first-line lorlatinib, and highlight gilteritinib as a potential therapeutic option for patients harboring this mutation. Notably, they also challenge the prevailing assumption that first-line lorlatinib precludes the emergence of single on-target ALK resistance mutations.