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Ref Type Journal Article
PMID (42129432)
Authors Nagasaka M, Facchinetti F, Bigot L, Brayé F, Groves MR, Yosa J, Wekken AV, Aldea M, Besse B, Planchard D, Naltet C, Katayama R, Olaussen KA, Loriot Y, Friboulet L
Title The novel ALK K1150dup mutation mediates resistance to frontline lorlatinib and retains sensitivity to gilteritinib.
Journal Vol Issue Date Pages Journal Short Title
NPJ precision oncology 2026 May 13 NPJ Precis Oncol
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ALK K1150dup duplication unknown ALK K1150dup indicates the insertion of the duplicate amino acid, lysine (K)-1150, in the protein kinase domain of the Alk protein (UniProt.org). K1150dup has been demonstrated to confer drug resistance in culture (PMID: 42129432), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2026).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK K1150dup Advanced Solid Tumor resistant NVL-655 Preclinical - Cell culture Actionable In a preclinical study, cells expressing ALK K1150dup in the context of EML4-ALK were resistant to NVL-655 treatment in culture (PMID: 42129432). 42129432
EML4 - ALK ALK K1150dup Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing ALK K1150dup in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 42129432). 42129432
EML4 - ALK ALK K1150dup lung adenocarcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, ALK K1150dup was identified at the time of progression on Lorbrena (lorlatinib) in a patient with lung adenocarcinoma harboring EML4-ALK (PMID: 42129432). 42129432
EML4 - ALK ALK L1196M ALK D1203N Advanced Solid Tumor resistant NVL-655 Preclinical - Cell culture Actionable In a preclinical study, cells expressing ALK D1203N and L1196M in the context of EML4-ALK were resistant to NVL-655 treatment in culture (PMID: 42129432). 42129432