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Cancer Discov. 2018 Apr 12. pii: CD-17-1256. doi: 10.1158/2159-8290.CD-17-1256. [Epub ahead of print]

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer.

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Cancer Center, Massachusetts General Hospital.
Broad Institute of MIT and Harvard.
Worldwide Research and Development, Pfizer.
INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay.
Department of Medicine, Massachusetts General Hospital.
Department of Pathology, Massachusetts General Hospital.
Novartis Institutes for BioMedical Research.
Cancer Center, Massachusetts General Hospital


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, ENU mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant 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.

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