High Tumor Mutation Burden and DNA Repair Gene Mutations are Associated with Primary Resistance to Crizotinib in -Rearranged Lung Cancer.

Onco Targets Ther

Department of Thoracic Oncology, State Key Laboratory of Respiratory Diseases, National Clinical Research Center of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People's Republic of China.

Published: September 2021

Background: About 20% of patients with -rearranged non-small cell lung cancer (NSCLC) develop acquired resistance to tyrosine kinase inhibitor (TKI) during the first 6 months. This study aimed to examine the molecular mechanisms of early TKI resistance and prognosis in -rearranged NSCLC.

Methods: Ten patients with -rearranged NSCLC were included: five who developed rapid resistance to crizotinib (progression-free survival (PFS) ≤3 months) and five who exhibited a good response to crizotinib (PFS ≥36 months). The tumor specimens were subjected to whole-exome sequencing (WES). The validation cohort included 19 patients with -rearranged NSCLC who received crizotinib; targeted sequencing of 43 selected genes was performed. The effect of the G245S mutation on crizotinib sensitivity was tested in H3122 cells.

Results: Mutations in DNA repair-associated genes were identified in primary resistance to crizotinib. Patients with a poor response to crizotinib harbored a greater burden of somatic mutations than those with a good response [median somatic mutations, 136 (range, 72-180) vs 31 (range, 10-48)]. Compared with the patients carrying wild-type or exon 3 deletion, 29 patients with G245S mutation showed a shorter survival time (P < 0.05), with a median PFS of 3 (95% CI: 1.9-4.1) months and a median overall survival of 7 (95% CI: 3.4-10.5) months. mutation promoted the proliferation of -rearranged H3122 cells by approximately 3 folds (P < 0.001). H3122 cells with mutant were more sensitive to crizotinib compared with control cells.

Conclusion: A higher mutation burden and mutations in DNA repair gene, including , were potentially associated with primary resistance to crizotinib in -rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in -rearranged NSCLC.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450189PMC
http://dx.doi.org/10.2147/OTT.S325443DOI Listing

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