期刊
CLINICAL CANCER RESEARCH
卷 27, 期 5, 页码 1410-1420出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-2853
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资金
- JSPS KAKENHI [18K15922]
- AMED [JP16ck0106041, JP18ck0106411, 15Ack0106147h0001, 18ck0106423h0001]
- Grants-in-Aid for Scientific Research [18K15922] Funding Source: KAKEN
Concurrent TP53 mutations were found to reduce the efficacy of alectinib in ALK-rearranged NSCLC, while the combination of a proteasome inhibitor with alectinib showed promising results in inducing apoptosis in preclinical models, indicating a potential therapy for ALK-rearranged/TP53-mutated NSCLC.
Purpose: In ALK-rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms. Experimental Design: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs. Results: In 90 patients with ALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, TP53 comutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); P = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. ALK-rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with nonfunctional p53. Conclusions: These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC.
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