Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.
Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.
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DOI：
10.4161/auto.32135
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发表时间：
2014-10-01
期刊：
影响因子：
13.3
通讯作者：
Thorburn A
中科院分区：
文献类型：
--
作者：
Morgan MJ;Gamez G;Menke C;Hernandez A;Thorburn J;Gidan F;Staskiewicz L;Morgan S;Cummings C;Maycotte P;Thorburn A
氯喹 (CQ) 是一种抗疟药和自噬后期抑制剂，目前 FDA 批准用于治疗类风湿关节炎和其他自身免疫性疾病。主要基于其抑制自噬的能力，CQ 及其衍生物羟氯喹目前正在多个癌症治疗临床试验中作为主要或辅助疗法进行研究。致癌 RAS 此前已被证明可以调节自噬通量，而 RAS 突变发生率高的癌症（例如胰腺癌）在文献中被描述为对 CQ 治疗特别敏感，从而导致了致癌 RAS 使癌细胞依赖自噬的假设。这种自噬“成瘾”表明肿瘤中 RAS 的突变状态可以识别哪些患者更有可能从 CQ 治疗中受益。在这里，我们表明 RAS 突变状态本身不太可能对此类患者选择有利，因为致癌 RAS 并不总是促进自噬成瘾。此外，致癌 RAS 对不同细胞的自噬通量和 CQ 敏感性具有相反的影响。最后，对于任何给定的细胞类型，致癌 RAS 对自噬的正面或负面影响并不一定能预测 RAS 是否会促进或抑制 CQ 介导的毒性。因此，尽管我们的结果证实不同的肿瘤细胞系对自噬抑制的反应表现出显着差异，但无论 RAS 突变状态如何，这些差异都可能发生，并且在不同的情况下，可以促进或降低肿瘤细胞对氯喹的敏感性。
Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy “addiction” suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.
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