Abstract
Crizotinib is an effective drug for patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), but upon treatment, the tumors inevitably become crizotinib resistant in time. The resistance mechanisms are only partly understood. In this study, we aim to identify gene mutations associated with resistance in ALKpositive advanced non-squamous NSCLC treated with crizotinib. Four ALK positive patients with progressive disease following crizotinib treatment were identified with paired pre- and post-crizotinib tumor tissue from our previously published cohort. Somatic variants in these samples were detected by whole exome sequencing. In one of the four patients, an ALK-resistance associated mutation was identified. In the other three patients, no ALK-resistance associated mutations were present. In these patients we identified 89 relevant somatic mutations in 74 genes that were specific to the resistant tumors. These genes were enriched in 15 pathways. Four pathways, were related to epithelial-mesenchymal transition (EMT): proteoglycans in cancer, HIF-1 signaling, FoxO signaling pathway, and ECM-receptor interaction. Analysis of other EMT-related pathways revealed three additional genes with mutations specific to the crizotinib-resistant tumor samples. The enrichment of mutations in genes associated with EMT-related pathways indicates that loss of epithelial differentiation may represent a relevant resistance mechanism for crizotinib.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide [1]
We aimed to identify somatic mutations related to crizotinib resistance using whole exome sequencing (WES) of paired tumor biopsies from advanced adenocarcinoma patients, taken both before crizotinib treatment and upon disease progression to crizotinib
ALK4 was treated with ceritinib and ALK14 with alectinib
Summary
In the traditional clinical classification, there are two major types of lung cancer, small cell lung cancer, and non-small-cell lung carcinoma (NSCLC) [2]. Clinical management and treatment of lung cancer patients has become more dependent on molecular classification using “driver” mutations that occur in genes, Cancers 2018, 10, 10; doi:10.3390/cancers10010010 www.mdpi.com/journal/cancers. Around 5% of all adenocarcinomas have a chromosomal inversion or translocation that produces a fusion product consisting of the kinase domain of ALK combined with. Tumor cells with an ALK fusion are highly sensitive to tyrosine kinase inhibitors (TKIs) that target ALK, which include crizotinib and the second-generation ALK inhibitors, ceritinib, brigatinib, and alectinib [7,8,9,10]. Most patients will inevitably acquire resistance to ALK-TKI treatment, usually within one year [11,12]
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