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Cancers 2018, 10(1), 10; https://doi.org/10.3390/cancers10010010

Mutations in EMT-Related Genes in ALK Positive Crizotinib Resistant Non-Small Cell Lung Cancers

1
Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands
2
Department of Pathology, Shantou University, Shantou 515041, China
3
Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands
4
Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands
5
Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 4 December 2017 / Revised: 22 December 2017 / Accepted: 29 December 2017 / Published: 4 January 2018
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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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. View Full-Text
Keywords: whole exome sequencing; adenocarcinoma; ALK; crizotinib resistance whole exome sequencing; adenocarcinoma; ALK; crizotinib resistance
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Wei, J.; van der Wekken, A.J.; Saber, A.; Terpstra, M.M.; Schuuring, E.; Timens, W.; Hiltermann, T.J.N.; Groen, H.J.M.; van den Berg, A.; Kok, K. Mutations in EMT-Related Genes in ALK Positive Crizotinib Resistant Non-Small Cell Lung Cancers. Cancers 2018, 10, 10.

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