抑制IGF-I通路克服多发性骨髓瘤对硼替佐米耐药的机制研究

It is very important to overcome bortezomib resistance in multiple myeloma (MM) for improving their therapeutic effect. We found that remission rate of patients with high expression of insulin-like growth factor-I receptor (IGF-IR) to bortezomib was low, while the mechanism remained unknown. IGF-I protects cells from endoplasmic reticulum stress-induced (ERS-induced) apoptosis via enhancement of the adaptive capacity of ERS, which is one of the most important mechanism for bortezomib to antagonise MM. Our previous research suggested that ERS-induced apoptosis was markedly reduced by IGF-I in myeloma cells and inhibition of IGF-IR could amplify the effect of bortezomib to inhibit growth and induce apoptosis in myeloma cell lines with high expression of IGF-IR. So we put forward the hypothesis that MM cells with high expression of IGF-IR might be resistant to bortezomib because of the modulation of ERS by IGF-I and inhibition of IGF-I pathway would restore myeloma sensitivity to bortezomib by attenuating adaptive capacity of ER by IGF-I. We propose to use technology of tetracycline-regulator control system, siRNA and differential proteomics to prove that ERS adaption by IGF-I in MM with high expression of IGF-IR is associated with bortezomib resistance in MM.This research will reveal the role of IGF-I pathway in bortezomib resistance, and provide more sufficient scientific evidence for the use of IGF-IR inhibitor to reverse bortezomib resistance in MM.

克服多发性骨髓瘤（MM）对硼替佐米（BOR）的耐药对提高MM的疗效非常重要。我们发现高表达胰岛素样生长因子-I受体(IGF-IR)的MM患者对BOR疗效不佳，其机制未明。目前认为IGF-I可调节ERS保护细胞，后者是BOR抗MM的重要机制。前期研究发现IGF-I可以拮抗ERS诱导剂诱导的细胞凋亡，抑制IGF-IR可增强BOR对高表达IGF-IR MM的作用。由此我们提出：“高表达IGF-IR的MM可通过IGF-I通路调节ERS导致其对BOR耐药。抑制该通路可以削弱ERS和UPR的代偿能力，克服MM对BOR的耐药”。本项目拟采用多西环素调控系统、siRNA技术、差异蛋白质组学等方法，旨在获得IGF-I调节高表达IGF-IR MM的ERS导致其对BOR耐药的证据并深入探讨其机制。本课题将阐明IGF-IR在MM耐BOR中的作用，为应用IGF-IR抑制剂克服MM对BOR耐药提供更充分的科学依据。

克服多发性骨髓瘤（MM）对硼替佐米(BOR)的耐药对提高MM的疗效非常重要。我们在临床中发现高表达胰岛素样生长因子-I受体（IGF-IR）的MM对BOR耐药，其机制未明。目前认为IGF-I可调节ERS保护细胞，而ERS正是BOR抗MM的最重要机制之一。前期实验发现IGF-I可以拮抗ERS诱导剂诱导的细胞凋亡，抑制IGF-IR可增强BOR对高表达IGF-IR MM细胞株的作用。由此我们提出一个假说：高表达IGF-IR的MM可以通过IGF-I增强内质网的代偿能力，对BOR耐药；抑制该通路可削弱ERS的代偿能力，逆转MM对BOR的耐药。通过本研究，我们证实了IGF-1R的表达与MM患者对硼替佐米的敏感性相关，抑制IGF-1R可以克服MM对BTZ耐药。进一步研究其机制时，我们发现部分MM细胞即使高表达IGF-1R，对硼替佐米仍较敏感，但其XBP-1s的激活程度有影响，提示IRE1α/Xbp-1通路不能被硼替佐米持续抑制可能参与了骨髓瘤耐药性的形成。本研究为克服硼替佐米耐药提供了理论基础及可能靶点。