Mutations in EMT-Related Genes in ALK Positive Crizotinib Resistant Non-Small Cell Lung Cancers.
Jiacong WeiAnthonie J van der WekkenAli SaberMiente M TerpstraEd SchuuringWim TimensT Jeroen N HiltermannHarry J M GroenAnke van den BergKlaas KokPublished in: Cancers (2018)
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.
Keyphrases
- advanced non small cell lung cancer
- epithelial mesenchymal transition
- end stage renal disease
- newly diagnosed
- signaling pathway
- ejection fraction
- epidermal growth factor receptor
- peritoneal dialysis
- chronic kidney disease
- stem cells
- randomized controlled trial
- genome wide
- emergency department
- systematic review
- pi k akt
- multiple sclerosis
- squamous cell carcinoma
- gene expression
- oxidative stress
- patient reported
- single cell
- high grade
- dna methylation
- bone marrow
- drug induced
- endoplasmic reticulum stress
- extracellular matrix
- transcription factor
- lymph node metastasis