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Updated: Oct 19, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
High Tumor Mutation Burden and DNA Repair Gene Mutations are Associated with Primary Resistance to Crizotinib in
Dakai Xiao1, Qiuhua Deng1, Dongyun He2
1Research Center forTranslational Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People's Republic of China.
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.
Insights
High mutation burden and DNA repair gene mutations, including TP53, are linked to primary resistance in ALK-rearranged NSCLC. TP53 mutations may affect survival and proliferation, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- 20% of ALK-rearranged NSCLC patients develop resistance to TKIs within 6 months.
- Early TKI resistance mechanisms and prognosis in ALK-rearranged NSCLC require examination.
Purpose of the Study:
- To investigate molecular mechanisms of early TKI resistance in ALK-rearranged NSCLC.
- To analyze the prognostic impact of genetic mutations on TKI response.
Main Methods:
- Whole-exome sequencing (WES) and targeted sequencing of tumor specimens from patients with varying crizotinib responses.
- In vitro testing of TP53 G245S mutation effects on crizotinib sensitivity in H3122 cells.
Main Results:
- Mutations in DNA repair genes, including TP53, were associated with primary resistance to crizotinib.
- Patients with poor crizotinib response had a higher somatic mutation burden.
- TP53 G245S mutation correlated with shorter survival and increased cell proliferation, yet paradoxically increased sensitivity in vitro.
Conclusions:
- Elevated mutation burden and DNA repair gene mutations (e.g., TP53) may predict primary resistance to crizotinib in ALK-rearranged NSCLC.
- Immune-checkpoint inhibition could be a potential strategy to overcome primary crizotinib resistance.
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