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Genomic Aberrations in Crizotinib Resistant Lung Adenocarcinoma Samples Identified by Transcriptome Sequencing
Ali Saber1, Anthonie J van der Wekken2, Klaas Kok3
1Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Plos One
|April 6, 2016
Summary
Resistance to crizotinib in ALK-positive non-small cell lung cancer is common. New ALK mutations, not fusion genes, were identified as the likely cause of resistance in this study.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Anaplastic Lymphoma Kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients initially benefit from crizotinib treatment.
- Acquired resistance to crizotinib is a significant clinical challenge, necessitating further investigation into its underlying mechanisms.
Purpose of the Study:
- To identify novel fusion genes in tumor samples from patients who developed resistance to crizotinib.
- To investigate the role of these fusion genes and known resistance-associated mutations in acquired crizotinib resistance.
Main Methods:
- Paired-end RNA sequencing was performed on re-biopsied tumor samples from three crizotinib-resistant NSCLC patients.
- Bioinformatic tools (deFuse, EricScript) were used for fusion gene identification, and the IGV browser for mutation analysis.
- Sanger sequencing and digital droplet PCR were employed for validation of identified fusion genes and mutations.
Main Results:
- ALK fusion genes, with EML4 as the common partner, were detected in all three patients' post-treatment samples and were also present in their pre-treatment biopsies.
- Additional fusion genes were identified in two patients, but only CLIP4-VSNL1 possessed a predicted open reading frame (ORF).
- Acquired ALK mutations (p.C1156Y and p.G1269A) were detected in two patients' post-treatment samples but were absent in their pre-treatment biopsies.
Conclusions:
- The identified fusion genes are unlikely to be the primary drivers of crizotinib resistance, as they were present before treatment initiation.
- Acquired mutations in ALK are strongly implicated as the mechanism conferring resistance to crizotinib in NSCLC patients.
