多发性骨髓瘤细胞对硼替佐米耐药机制的研究进展

Research Progress on Molecular Mechanisms of Resistance to Bortezomib in Multiple Myeloma

近十年来,硼替佐米(bortezomib,BTZ)在血液恶性肿瘤尤其是多发性骨髓瘤(multiple myeloma,MM)和套细胞淋巴瘤(mantle cell lymphoma,MCL)的治疗中起到了非常重要的作用,尽管如此,继发性耐药的出现为该药物的临床使用带来了很大的挑战。本文根据近年来对硼替佐米耐药机制的研究现状,从泛素蛋白酶体系统(ubiquitin-proteasome system,UPS)的作用、内质网应激通路、自噬作用、细胞促存活信号通路和骨髓微环境等方面作一综述,并探讨耐药机制中可能存在的新的治疗策略。近年来随着对耐药机制的不断研究,新的组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors,HDACi)已经被用于MM的治疗,AKT抑制剂也处于临床试验阶段,这些新的联合治疗方法有望增强硼替佐米的疗效,改善患者的预后。

Over the last decade,bortezomib（BTZ） has been extensively applied in the treatment of hematological malignancies,particularly in multiple myeloma and mantle cell lymphoma,however,the appearence of secondary resistance to BTZ has brought a huge challenge in MM treatment. In the present review,the mechanisms of resistance to bortezomib in MM are summarized,focusing on the action of ubiquitin-proteasome system（ UPS）,endoplasmin reticulum stress,antophagy,inducible pro-survival signalling and bone marrow microenvironment as well as exploration of the potential therapeutic strategies in the clinical perspective. With the understanding of the molecular mechanisms for resistance to BTZ,the novel histone deacetylase inhibitors（HDACi） have been approved for the treatment of replased/refractory MM and AKT inhibitor in the clinical trials. These novel combined therapies can enhance BTZ efficiency and improve the outcome of the patients.