Acosta-Alvear Diego, Cho Min Y, Wild Thomas, Buchholz Tonia J, Lerner Alana G, Simakova Olga, Hahn Jamie, Korde Neha, Landgren Ola, Maric Irina, Choudhary Chunaram, Walter Peter, Weissman Jonathan S, Kampmann Martin
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
Howard Hughes Medical Institute, San Francisco, United States.
Elife. 2015 Sep 1;4:e08153. doi: 10.7554/eLife.08153.
Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.
癌症的特征，包括快速生长和非整倍体，可导致对蛋白质稳态网络产生非癌基因成瘾，而这一点可在临床上加以利用。典型的例子是多发性骨髓瘤（MM）对20S蛋白酶体抑制剂（如卡非佐米）极为敏感。然而，MM患者总会对这些药物产生耐药性。利用新一代短发夹RNA（shRNA）平台，我们发现蛋白质稳态因子，包括伴侣蛋白和应激反应调节因子，控制着对卡非佐米的反应。矛盾的是，19S蛋白酶体调节因子的敲低在MM细胞和非MM细胞中诱导了对卡非佐米的耐药性。19S亚基的敲低并不影响卡非佐米靶向的20S亚基的活性，也不影响药物对它们的抑制作用，提示存在另一种机制，如保护性因子的选择性积累。在MM患者中，较低的19S水平预示着对基于卡非佐米的治疗反应减弱。总之，我们的研究结果表明，对网络重塑的理解可为开发新的联合疗法以克服耐药性提供依据。
