联合靶向CDK4/6和MVA途径诱导细胞铁死亡的新机制及其在KRAS突变型肠癌治疗中的意义

帕博西尼等CDK4/6抑制剂已被FDA批准用于ER+/HER2-晚期乳腺癌的治疗，其在KRAS突变型肠癌中也呈现出潜在的临床应用前景，然而关于其动态作用后的耐药机制尚不清楚，亟待解决。项目组的前期工作显示，在KRAS突变型肠癌细胞中，帕博西尼长时间处理会引起细胞周期相关蛋白的表达升高，同时也会激活甲羟戊酸(MVA)途径；联合使用帕博西尼和MVA途径的抑制剂可协同诱导细胞的铁死亡。该项目拟进一步对帕博西尼长时间处理诱导P27-CDK4/6-CyclinD1复合体的形成继而激活SREBPs-MVA途径的机制；联合帕博西尼和MVA途径的抑制剂诱导细胞铁死亡的新机制及多种联合治疗方案的体内疗效等方面进行深入系统的研究。该项目将为我们深入认识CDK4/6抑制剂在KRAS突变型肠癌中的动态作用机制提供新的视角，并为KRAS突变型肠癌的靶向治疗提供多种新的联合治疗策略。

Palbociclib and several other CDK4/6 inhibitors have been approved by the FDA for the treatment of estrogen receptor-positive, HER2-negative, .advanced breast cancer, they have also presented potential prospect of clinical application in the KRAS mutant colon cancers. However, the resistant mechanisms about the dynamic effect of palbociclib remain elusive in colon cancer, and urgently need to be solved. Our preliminary work showed that in the KRAS mutant colon cancer cells, long-time palbociclib treatment induced the overexpression of the cell cycle related proteins, and caused the activation of the mevalonate pathway. Further combined use of palbociclib and the mevalonate pathway inhibitors synergistically induced cell ferroptosis. In this project, we will further investigate the underlying mechanism about: how the long-time palbociclib treatment induces formation of P27-CDK4/6-CyclinD1 complex, which will further activate the SREBPs-MVA pathway; the ferroptosis induced by the combination of palbociclib and the MVA pathway inhibitors; and the efficacy of several combined therapeutic strategies in vivo. This project will provide us new perspectives for our deeply understanding the dynamic effect of palbociclib in KRAS mutant colon cancer cells, and present several novel combined therapeutic strategies for the targeted treatment of KRAS mutant colon cancers.