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.



中文翻译：

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高肿瘤突变负担和 DNA 修复基因突变与 ALK 重排肺癌对克唑替尼的原发性耐药有关

背景：大约 20% 的ALK重排非小细胞肺癌 (NSCLC) 患者在前 6 个月内对酪氨酸激酶抑制剂 (TKI) 产生获得性耐药。本研究旨在探讨ALK重排 NSCLC 早期 TKI 耐药和预后的分子机制。
方法：纳入10名ALK重排 NSCLC 患者：5 名对克唑替尼产生快速耐药（无进展生存期 (PFS) ≤ 3 个月）和 5 名对克唑替尼表现出良好反应（PFS ≥ 36 个月）。对肿瘤标本进行全外显子组测序（WES）。验证队列包括 19名 ALK患者-接受克唑替尼治疗的重排非小细胞肺癌；对 43 个选定基因进行了靶向测序。在 H3122 细胞中测试了TP53 G245S 突变对克唑替尼敏感性的影响。
结果：在对克唑替尼的原发性耐药中发现了 DNA 修复相关基因的突变。对克唑替尼反应不佳的患者比反应良好的患者具有更大的体细胞突变负担[中位体细胞突变，136（范围，72-180）vs 31（范围，10-48）]。与携带野生型TP53或TP53外显子 3 缺失的患者相比，29名TP53G245S 突变显示更短的生存时间 (P < 0.05)，中位 PFS 为 3 (95% CI: 1.9–4.1) 个月，中位总生存期为 7 (95% CI: 3.4–10.5) 个月。TP53突变促进了EML4-ALK重排的 H3122 细胞的增殖大约 3 倍（P < 0.001）。与对照细胞相比，具有TP53突变体的H3122 细胞对克唑替尼更敏感。
结论：较高的突变负担和包括TP53在内的 DNA 修复基因突变可能与ALK重排 NSCLC 对克唑替尼的原发性耐药相关。可以检查免疫检查点抑制策略，这可能会克服ALK中对克唑替尼的原发性耐药性-重排非小细胞肺癌。