State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Clin Cancer Res. 2018 Dec 1;24(23):6066-6077. doi: 10.1158/1078-0432.CCR-18-1478. Epub 2018 Jul 30.
The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized.
Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models.
We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by ), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including -mutant, -altered, and -rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models.
These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics.
致癌基因抑制后诱导的死亡信号是分子靶向治疗人类癌症临床疗效的基础，而完整细胞凋亡机制的缺陷常常导致治疗失败。尽管具有潜在的重要性，但其他形式的受药物干预触发的调节性细胞死亡尚未得到系统的描述。
通过免疫印迹分析、相差成像、扫描电子显微镜和流式细胞术评估细胞焦亡。使用免疫组化分析肺癌患者的肿瘤组织。在细胞系和异种移植模型中研究细胞焦亡对药物反应的功能影响。
我们表明，多种针对 KRAS、EGFR 或 ALK 驱动的肺癌的小分子抑制剂特异性地引发了强烈的细胞焦亡，同时也引发了细胞凋亡。在药物治疗后，线粒体内在凋亡途径被激活，被募集的半胱天冬酶-3 蛋白酶切割并激活了 GSDME（由编码），这导致细胞质膜穿孔并执行细胞裂解性细胞焦亡。GSDME 在各种肺癌细胞系和临床标本中广泛表达，包括 -突变、-改变和 -重排的腺癌。因此，凋亡和细胞焦亡的共发生和相互作用在肺癌细胞中广泛存在，对与基因型匹配的方案产生反应。我们进一步证明，细胞焦亡在一部分癌症模型中对药物反应有一定的贡献。
这些结果指出，GSDME 依赖性细胞焦亡是分子靶向药物根除致癌基因依赖性肿瘤细胞的一种以前未被认识的作用机制，这可能对癌症治疗药物的临床开发和最佳应用具有重要意义。
