Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas

Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such a heterogeneity presents a significant challenge in preventing tumor recurrence. In the current study, we observed that quiescent CUB-domain–containing protein 1 (CDCP1)+ CSCs are enriched after chemotherapy in mutant Kirsten rat sarcoma viral oncogene homolog (Kras) colorectal carcinomas (CRCs) and serve as a reservoir for recurrence. Mechanistically, glucose catabolism in CDCP1+ CSCs is routed to the oxidative pentose phosphate pathway (PPP); multiple cycling of carbon backbones in the oxidative PPP potentially maximizes NADPH reduction to counteract chemotherapy-induced reactive oxygen species (ROS) formation, thereby allowing CDCP1+ CSCs to survive chemotherapeutic attack. This is dependent on silent mating type information regulation 2 homolog 5 (Sirt5)-mediated inhibition of the glycolytic enzyme triosephosphate isomerase (TPI) through demalonylation of Lys56. Blocking demalonylation of TPI at Lys56 increases chemosensitivity of CDCP1+ CSCSs and delays recurrence of mutant Kras CRCs in vivo. These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs.复发性肿瘤起源于在常规治疗中存活的癌症干细胞（Cancer Stem Cells, CSCs）。癌症干细胞包含异质性亚群，这些亚群对抗癌药物展现出不同的敏感性。这种异质性为预防肿瘤复发带来了重大挑战。在本研究中，我们观察到，在突变型Kirsten大鼠肉瘤病毒癌基因同源物（Kirsten rat sarcoma viral oncogene homolog, Kras）结直肠癌（colorectal carcinomas, CRCs）中，经化疗后富集的静息CUB结构域包含蛋白1（CUB-domain-containing protein 1, CDCP1）阳性癌症干细胞，是肿瘤复发的储存库。从机制上而言，CDCP1阳性癌症干细胞的葡萄糖分解代谢流向氧化型磷酸戊糖途径（oxidative pentose phosphate pathway, PPP）；氧化型磷酸戊糖途径中碳骨架的多次循环，可最大化还原型烟酰胺腺嘌呤二核苷酸磷酸（Nicotinamide Adenine Dinucleotide Phosphate, NADPH）的还原当量生成，以抵消化疗诱导的活性氧（Reactive Oxygen Species, ROS）产生，从而使CDCP1阳性癌症干细胞能够在化疗攻击下存活。这一过程依赖于沉默信息调节因子2同源物5（silent mating type information regulation 2 homolog 5, Sirt5）介导的糖酵解酶磷酸丙糖异构酶（triosephosphate isomerase, TPI）抑制，该抑制通过对第56位赖氨酸残基的去丙二酰化修饰实现。阻断第56位赖氨酸残基处TPI的去丙二酰化修饰，可增强CDCP1阳性癌症干细胞的化疗敏感性，并在体内延缓突变型Kras结直肠癌的复发。上述研究结果为对抗突变型Kras结直肠癌指明了全新的治疗策略。