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

Abstract

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.

The Effect of Feedback During Training Sessions on Learning Pattern-Recognition-Based Prosthesis Control

“…FASTQ files were obtained from the company and processed as previously described [22]. Briefly, reads were aligned to the hg19 reference genome with Burrows-Wheeler Aligner (BWA) and Genome Analysis Toolkit (GATK) [23].…”

NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 5.2018

“…[39][40][41][42] Ongoing studies are assessing the role of individual ALK kinase domain mutations in selecting subsequent therapy. 43,44 ROS1 Rearrangements: Although ROS1 is a distinct receptor tyrosine kinase, it is very similar to ALK. 45,46 ROS1 rearrangements occur in approximately 1% to 2% of patients with NSCLC, and occur more frequently in younger women (median age, 50 years) with adenocarcinoma who are never-smokers and in those negative for EGFR and KRAS mutations and ALK rearrangements.…”

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“…Proposed ALK-independent mechanisms of resistance include alteration in EGFR, mast/stem cell growth factor receptor (KIT) and insulin-like growth factor 1 receptor, and activation of phosphorylation-dependent signalling pathways 23–25. In an analysis of three patients resistant to crizotinib without ALK-resistance mutations, enrichment of nine genes in four EMT pathways were identified 26. Additionally, transformation to small cell lung cancer has been described as a rare mechanism of resistance 27.…”