Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2019 Jan 8;26(2):469-482.e5. doi: 10.1016/j.celrep.2018.12.043.
The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.
先前存在的调节回路的可塑性会影响靶向治疗的效果，而利用癌细胞中的遗传易损性可能会克服这些适应性。遗传性平滑肌瘤病肾细胞癌（HLRCC）的特征是由于延胡索酸水合酶（FH）纯合缺失而导致的氧化磷酸化（OXPHOS）缺陷。为了确定与 OXPHOS 缺陷具有合成致死性的代谢基因，我们进行了遗传功能丧失筛选，发现磷酸葡萄糖酸脱氢酶（PGD）抑制在体外和体内均能强烈抑制 FH 突变癌细胞的增殖。从机制上讲，PGD 抑制阻断糖酵解，抑制谷氨酰胺的还原羧化作用，并增加 NADP/NADPH 比值以破坏氧化还原平衡。此外，在 OXPHOS 功能正常的情况下，使用小分子抑制剂 IACS-010759 阻断 OXPHOS 会增强体外和体内对 PGD 抑制的敏感性。综上所述，我们的研究揭示了 OXPHOS 缺陷肿瘤对 PGD 的依赖性，这可能为特定患者群体的治疗干预提供信息。
