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

BACKGROUND: About 20% of patients with ALK-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 ALK-rearranged NSCLC. METHODS: Ten patients with ALK-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 ALK-rearranged NSCLC who received crizotinib; targeted sequencing of 43 selected genes was performed. The effect of the TP53 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 TP53 or TP53 exon 3 deletion, 29 patients with TP53 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. TP53 mutation promoted the proliferation of EML4-ALK-rearranged H3122 cells by approximately 3 folds (P < 0.001). H3122 cells with TP53 mutant were more sensitive to crizotinib compared with control cells. CONCLUSION: A higher mutation burden and mutations in DNA repair gene, including TP53, were potentially associated with primary resistance to crizotinib in ALK-rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in ALK-rearranged NSCLC.