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Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer
Soyeon Kim1, Tae Min Kim, Dong-Wan Kim
1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Background:
Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is markedly sensitive to the ALK inhibitor crizotinib. However, acquired resistance to crizotinib is inevitable through several mechanisms. Therefore, this study was conducted to identify genetic alterations associated with crizotinib resistance.
Methods:
Tumor samples were derived from seven ALK-positive NSCLC patients who showed acquired resistance to crizotinib, and these patients were analyzed for ALK, EGFR, and KRAS mutations and ALK and EGFR gene amplifications. In vitro cytotoxicity of crizotinib and ALK downstream signals were compared between crizotinib-naive and -resistant NSCLC cells.
Results:
After a median duration of 6 months (range, 4-12 months), seven ALK-positive NSCLC patients developed acquired resistance to crizotinib. Three patients harbored secondary ALK mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Of note, one patient displayed ALK gene copy number gain (4.1-fold increase compared with the pre-crizotinib specimen) and EGFR L858R mutation with high polysomy. The amphiregulin concentration was high in the supernatant fluid from five patients with malignant pleural effusion (116.4-18934.0 pg/ml). SNU-2535 cells derived from a patient who harbored the G1269 mutation were resistant to crizotinib treatment similar to H3122 CR1 cells. L1196M and G1269A mutant clones were less sensitive to crizotinib and ALK downstream signals were ineffectively suppressed in these clones.
Conclusions:
Genetic changes associated with crizotinib resistance are heterogeneous in ALK-rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance.
Insights
Acquired resistance to crizotinib in ALK-rearranged NSCLC is linked to diverse genetic alterations, including secondary ALK mutations and gene amplifications. Understanding these changes is key to overcoming treatment resistance.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) shows sensitivity to crizotinib.
- Acquired resistance to crizotinib is a significant clinical challenge in ALK-positive NSCLC patients.
Purpose of the Study:
- To identify genetic alterations driving acquired resistance to crizotinib in ALK-rearranged NSCLC.
- To understand the mechanisms of resistance to ALK inhibitors.
Main Methods:
- Analysis of tumor samples from seven ALK-positive NSCLC patients with acquired resistance to crizotinib.
- Genotyping for ALK, EGFR, and KRAS mutations, and ALK/EGFR gene amplifications.
- In vitro comparison of cytotoxicity and downstream signaling in crizotinib-naive and resistant NSCLC cells.
Main Results:
- Seven patients developed resistance after a median of 6 months.
- Secondary ALK mutations (L1196M, G1269A) were found in three patients.
- One patient exhibited ALK gene copy number gain and EGFR L858R mutation; high amphiregulin levels were observed in patients with malignant pleural effusion.
Conclusions:
- Genetic alterations conferring crizotinib resistance are heterogeneous in ALK-rearranged NSCLC.
- Secondary ALK mutations and gene amplifications contribute to acquired resistance.
- Further research is needed to develop strategies to overcome crizotinib resistance.
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