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

Abstract

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.

Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial

“…The gene mutation landscape showed that the most common co-mutation genes of ALK positive patients in our study were TP53 and KMT2C, which were reported functions in cell proliferation, tumor formation and DNA damage repair ( 30 - 34 ). At baseline, patients with TP53 mutation had higher gene mutation load, which was reported associated with primary resistance to crizotinib in ALK+ NSCLC ( 35 ). We found that patients with low ALK mutation abundance at baseline achieved significantly longer mPFS compared to those with high ALK mutation abundance.…”

Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

“…Since there are few studies on primary resistance to ALK TKIs, the potential mechanism of drug resistance is not yet clear. Several case reports revealed possible intrinsic factors of primary resistance to crizotinib, including MYC amplification [ 195 ], ALK/KRAS co-alteration [ 196 , 197 ], Bim deletion polymorphism [ 198 ], high tumor mutational burden (TMB), and mutations in DNA repair genes (including TP53 G245S) [ 199 ]. More efforts should be made to explore the mechanisms of primary resistance to improve the treatment efficiency of these patients.…”