Targeting RIP3-mediated Necroptosis for Chemosensitization

 描述（由申请人提供）：由于化疗耐药性，化疗通常对肺癌无效。化疗药物的抗癌活性主要是通过杀死癌细胞。对凋亡耐药相关机制的巨大努力已经适度改善了肺癌化疗，表明其他机制在化疗耐药中至关重要。最近的研究表明，治疗剂可以诱导RIP 3介导的坏死性凋亡，以杀死对凋亡有抗性的肿瘤细胞。然而，癌细胞可能发展出逃避坏死的能力。我们的初步研究发现：（1）RIP 3表达在22%的人肺癌组织中受到抑制;（2）RIP 3启动子高甲基化与RIP 3抑制相关;（3）恢复RIP 3表达显著增加肺癌细胞对顺铂的敏感性;（4）强制RIP 3表达增强顺铂诱导的坏死性凋亡;（5）致敏坏死性凋亡增加化疗敏感性。因此，我们假设在某些人肺癌中坏死性凋亡途径受损，并且致敏坏死性凋亡将提高这些肺癌的化疗疗效并克服化疗耐药性。将在三个具体目的中检验该假设：（1）确定致敏性坏死性凋亡是否克服肺癌细胞中的化学抗性;（2）确定RIP 3的表观遗传和转录后调节是否是人肺癌中坏死性凋亡抑制相关的化学抗性的机制的基础;以及（3）确定RIP 3再表达是否使裸鼠中的人NSCLC异种移植物中的坏死性凋亡增敏并克服化学抗性。本申请的目的是获得更多支持性证据，验证坏死性凋亡在肺癌一线化疗临床反应和化疗耐药性中的作用。该项目的积极结果将为R 01应用提供坚实的基础，并进行全面的机制和转化研究，以提高化疗对肺癌的疗效。

 DESCRIPTION (provided by applicant): Chemotherapy is usually ineffective for lung cancer due to chemoresistance. The anticancer activity of chemotherapeutics is mainly through the killing of cancer cells. Tremendous efforts on apoptosis resistance-related mechanisms have moderately improved lung cancer chemotherapy, suggesting other mechanisms are critical in chemoresistance. Recent studies suggest that therapeutics can induce RIP3- mediated necroptosis to kill tumor cells that are resistant to apoptosis. However, cancer cells may develop necroptosis-evading capacities. Our preliminary studies found: (1) RIP3 expression is suppressed in 22% of human lung cancer tissues; (2) RIP3 promoter hypermethylation is associated with RIP3 suppression; (3) restoring RIP3 expression significantly increased sensitivity of lung cancer cells to cisplatin; (4) forced RIP3 expression enhanced cisplatin-induced necroptosis; and (5) sensitizing necroptosis increased chemosensitivity. Thus, we hypothesize that the necroptosis pathway is impaired in some human lung cancers and sensitizing necroptosis will improve chemotherapy efficacy and overcome chemoresistance in these lung cancers. The hypothesis will be tested in three specific aims: (1) To determine if sensitizing necroptosis overcomes chemoresistance in lung cancer cells; (2) To determine if epigenetic and post- transcriptional regulation of RIP3 underlies the mechanisms of necroptosis suppression-associated chemoresistance in human lung cancer; and (3) To determine if RIP3 re-expression sensitizes necroptosis and overcomes chemoresistance in human NSCLC xenografts in nude mice. The goal of this application is to obtain more supportive evidence validating the role of necroptosis in lung cancer's clinical response to first-line chemotherapy and chemoresistance. Positive results from this project will be a solid foundation for an R01 application with comprehensive mechanistic and translational studies for improving the efficacy of chemotherapy against lung cancer.