Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression
Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression
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DOI：
10.1158/1078-0432.ccr-20-2853
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发表时间：
2021-03-01
影响因子：
11.5
通讯作者：
Yano，Seiji
中科院分区：
文献类型：
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作者：
Tanimoto，Azusa;Matsumoto，Shingo;Yano，Seiji
目的在 ALK 重排非小细胞肺癌 (NSCLC) 中，伴随基因改变对 ALK 酪氨酸激酶抑制剂 (ALK-TKI) 靶向治疗的影响尚不清楚。在这里，我们利用临床基因组数据研究了与 ALK-TKI 耐药相关的基因改变，并通过识别潜在的分子机制探索了克服临床前模型中耐药性的有效疗法。实验设计我们使用了全国性肺癌基因组筛查项目 (LC-SCRUM-Japan) 中生成的综合临床和下一代测序数据。表达野生型或突变型 TP53 的 ALK 重排 NSCLC 细胞系用于评估 ALK-TKI 诱导的细胞凋亡。 90 名接受选择性 ALK-TKI、艾来替尼、TP53 突变型患者治疗的 90 名 ALK 重排 NSCLC 患者的无进展生存期 (PFS) 显着差于 TP53 野生型患者 [中位 PFS，11.7 个月（95% 置信区间，CI，6.3 – 未达到，NR）与 NR (23.6 – NR) 相比；P= 0.0008； HR, 0.33 (95% CI, 0.17–0.65)]。失去 p53 功能的 ALK 重排 NSCLC 细胞系对艾来替尼诱导的细胞凋亡具有抵抗力，但蛋白酶体抑制剂伊沙佐米通过增加与抗凋亡蛋白 Mcl-1 结合的促凋亡蛋白 Noxa 的表达，显着诱导艾来替尼治疗的细胞凋亡。在皮下肿瘤模型中，伊沙佐米和艾乐替尼的组合显着诱导肿瘤消退和细胞凋亡，即使肿瘤是由具有非功能性 p53 的 ALK 重排 NSCLC 细胞产生的。结论这些临床和临床前结果表明，伴随的 TP53 突变降低了艾乐替尼治疗 ALK 重排 NSCLC 的疗效，蛋白酶体抑制剂与艾乐替尼的联合使用是一种有前景的治疗方法适用于 ALK 重排/TP53 突变 NSCLC。
PurposeInALK-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 DesignWe 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 mutantTP53were used to evaluate cellular apoptosis induced by ALK-TKIs.ResultsIn 90 patients withALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib,TP53comutated patients showed significantly worse progression-free survival (PFS) thanTP53wild-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 fromALK-rearranged NSCLC cells with nonfunctional p53.ConclusionsThese clinical and preclinical results indicate concomitantTP53mutations reduce the efficacy of alectinib forALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy forALK-rearranged/TP53-mutated NSCLC.