Ruan Hang, Leibowitz Brian J, Peng Yingpeng, Shen Lin, Chen Lujia, Kuang Charlie, Schoen Robert E, Lu Xinghua, Zhang Lin, Yu Jian
UPMC Hillman Cancer Center Research Pavilion, Suite 2.26h, 5117 Centre Ave., Pittsburgh, PA, 15213, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
Mol Biomed. 2022 Mar 21;3(1):10. doi: 10.1186/s43556-022-00070-7.
Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc translation and Myc-dependent stress adaptation and proliferation. Here, we report that the combination of two FDA-approved drugs Bortezomib and Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC cells. Mechanistically, the combination, not single agent, rapidly depletes Myc protein, not mRNA, and leads to GCN2- and p-eIF2α-dependent cell death through the activation of extrinsic and intrinsic apoptotic pathways. Cell death is selectively induced in mutant KRAS CRC cells with elevated basal Myc and p-eIF2α and is characterized by CHOP induction and transcriptional signatures in proteotoxicity, oxidative stress, metabolic inhibition, and immune activation. BR-induced p-GCN2/p-eIF2α elevation and cell death are strongly attenuated by MYC knockdown and enhanced by MYC overexpression. The BR combination is efficacious against mutant KRAS patient derived organoids (PDO) and xenografts (PDX) by inducing p-eIF2α/CHOP and cell death. Interestingly, an elevated four-gene (DDIT3, GADD45B, CRYBA4 and HSPA1L) stress signature is linked to shortened overall survival in CRC patients. These data support that Myc-dependent stress adaptation drives the progression of mutant KRAS CRC and serves as a therapeutic vulnerability, which can be targeted using dual translational inhibitors.
突变型KRAS是结直肠癌（CRC）的关键驱动因素，可促进Myc的翻译以及Myc依赖性应激适应和增殖。在此，我们报告美国食品药品监督管理局（FDA）批准的两种药物硼替佐米和依维莫司（RAD001）（BR）联合使用对突变型KRAS CRC细胞具有高效性。从机制上讲，联合用药而非单一药物能迅速消耗Myc蛋白而非mRNA，并通过激活外在和内在凋亡途径导致GCN2和磷酸化真核翻译起始因子2α（p-eIF2α）依赖性细胞死亡。在基础Myc和p-eIF2α升高的突变型KRAS CRC细胞中选择性诱导细胞死亡，其特征为CHOP诱导以及蛋白毒性、氧化应激、代谢抑制和免疫激活方面的转录特征。BR诱导的p-GCN2/p-eIF2α升高和细胞死亡通过MYC基因敲低而显著减弱，并通过MYC过表达而增强。BR联合用药通过诱导p-eIF2α/CHOP和细胞死亡，对源自突变型KRAS患者的类器官（PDO）和异种移植瘤（PDX）有效。有趣的是一种四基因（DDIT3、GADD45B、CRYBA4和HSPA1L）应激特征升高与CRC患者总生存期缩短相关。这些数据支持Myc依赖性应激适应驱动突变型KRAS CRC的进展并构成一种治疗易损性，可使用双重翻译抑制剂作为靶点。
