Herein we discuss multiple pre-clinical projects developed by our group that have been translated into patients at Massey Cancer Center. Our work has used multi-kinase inhibitors, for example, sorafenib, regorafenib and neratinib, and combined with additional agents, for example, histone deacetylase inhibitors, the thymidylate synthase inhibitor pemetrexed, and PDE5 inhibitors. In broad-brush terms, our experience has been that these drug combinations enhance signaling by ATM-AMPK-ULK-1 and decrease signaling from growth factor receptors and RAS proteins, thereby lowering the activities of the intracellular signaling kinase ERK1/2, AKT, mTOR and p70S6K. This collectively results in reduced protein synthesis and the induction of an endoplasmic reticulum stress response alongside autophagosome formation and autophagic flux. The rupture of autolysosomes, releasing proteases such as cathepsin B into the cytosol results in the cleavage and activation of the toxic BH3 domain protein BID which cooperates with BAX, BAK and BIM to cause mitochondrial dysfunction, leading to the release of cytochrome c and AIF, which then execute the tumor cell. For each of our two-drug combinations, we then performed additional laboratory-based studies to define the development of evolutionary resistance mechanisms, with the long-term concept of performing new three-drug clinical trials to prolong therapeutic efficacy and disease control.

中文翻译：

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自噬作为杀死耐药癌细胞的治疗机制。

在此，我们讨论了我们团队开发的多个临床前项目，这些项目已在梅西癌症中心转化为患者。我们的工作使用了多激酶抑制剂，例如索拉非尼、瑞戈非尼和来那替尼，并与其他药物联合使用，例如组蛋白脱乙酰酶抑制剂、胸苷酸合成酶抑制剂培美曲塞和 PDE5 抑制剂。从广义上讲，我们的经验是，这些药物组合增强了 ATM-AMPK-ULK-1 的信号传导，并减少了生长因子受体和 RAS 蛋白的信号传导，从而降低了细胞内信号传导激酶 ERK1/2、AKT、 mTOR 和 p70S6K。这共同导致蛋白质合成减少并诱导内质网应激反应以及自噬体形成和自噬流。自溶酶体破裂，将组织蛋白酶B等蛋白酶释放到胞浆中，导致有毒的BH3结构域蛋白BID裂解和激活，与BAX、BAK和BIM配合引起线粒体功能障碍，导致细胞色素c和AIF的释放，然后执行肿瘤细胞。然后，对于我们的每种两种药物组合，我们进行了额外的基于实验室的研究，以定义进化耐药机制的发展，并提出了进行新的三种药物临床试验以延长治疗效果和疾病控制的长期概念。