Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer

Satoshi Yoda, Jessica J. Lin, Michael S. Lawrence, Benjamin J. Burke, Luc Friboulet, Adam Langenbucher, Leila Dardaei, Kylie Prutisto-Chang, Ibiayi Dagogo-Jack, Sergei Timofeevski, Harper Hubbeling, Justin F. Gainor, Lorin A. Ferris, Amanda K. Riley, Krystina E. Kattermann, Daria Timonina, Rebecca S. Heist, A. John Iafrate, Cyril H. Benes, Jochen K. LennerzMari Mino Kenudson, Jeffrey A. Engelman, Ted W. Johnson, Aaron N. Hata, Alice T. Shaw

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    253 Citations (Scopus)

    Résumé

    The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4–ALK. Under comparable conditions, N -ethyl- N -nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinibresistant clones harboring single ALK mutations. In similar screens with EML4–ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies. SIGNIFICANCE: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance.

    langue originaleAnglais
    Pages (de - à)714-729
    Nombre de pages16
    journalCancer Discovery
    Volume8
    Numéro de publication6
    Les DOIs
    étatPublié - 1 juin 2018

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