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

Abstract 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.