Mcl-1介导的BRAF基因V600E突变结直肠癌针对mTOR抑制剂的耐药作用以及机制研究

mTOR pathway has been considered as a target for cancer therapy. Our recent work demonstrated that activation of ER stress and the induction of DR5 contributes significantly to apoptosis induced by mTOR inhibitors in colorectal cancer. In the meantime, the preliminary data showed that BRAF V600E colorectal cancer cells were less sensitive to mTOR inhibitor and the increasing of protein level of Mcl-1 might present the underlying mechanism..We propose to study the drug resistance of mTOR inhibitors in BRAF V600E colorectal cancer in both cell and animal based models, to explore whether the induction of Mcl-1 secondary to the change of phosphorylation of Mcl-1 by GSK3β or ERK antagonizes mTOR inhibitor-induced apoptosis. We will uncover a BRAFV600E/Mcl-1-dependent mechanism underlying intrinsic resistance to mTOR inhibitors. These findings will help the new mTOR inhibitor R&D, lay the foundation to help better design more accurate clinical trials.

mTOR信号通路被公认为有效的抗癌靶点。我们的前期研究首次发现了，在结直肠癌中，mTOR抑制剂通过激起内质网应激反应而上调死亡受体5（DR5），最终导致细胞凋亡。但是同时我们也观察到，BRAF基因V600E突变的结直肠癌细胞对mTOR抑制剂引起的细胞凋亡不敏感，其机制可能与Bcl-2家族抗细胞凋亡蛋白质Mcl-1蛋白水平上调有关。.本项目将以配对的BRAF基因野生型和V600E突变型结直肠癌细胞株为实验模型，在细胞和动物模型水平明确BRAF基因V600E突变对mTOR抑制剂的耐药作用，阐明GSK3β或者ERK介导的Mcl-1磷酸化，导致Mcl-1蛋白水平上调，拮抗mTOR抑制剂引起的的细胞凋亡。揭示Mcl-1介导的BRAF基因V600E突变结直肠癌对 mTOR抑制剂的耐药机制，为下一步研发新型mTOR抑制剂，指导以及优化mTOR抑制剂在临床中的精准使用奠定基础。