A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

• Published in: Blood 2014-10, Vol.124 (17), p.2687-2697
• Main Authors: Chen, Shuang, Zhang, Yu, Zhou, Liang, Leng, Yun, Lin, Hui, Kmieciak, Maciej, Pei, Xin-Yan, Jones, Richard, Orlowski, Robert Z., Dai, Yun, Grant, Steven
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; Autophagy - genetics; Autophagy - physiology; Bcl-2-Like Protein 11; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor; Cells, Cultured; Drug Resistance, Neoplasm - drug effects; Fluorescent Antibody Technique; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - pharmacology; Immunoblotting; Lymphoid Neoplasia; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrazines - pharmacology; RNA Interference; Tumor Burden - drug effects; Tumor Burden - genetics; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-03-564534

Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bimhi) in most MM cell lines and primary CD138+ MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bimhi cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bimhi cells. In Bimlow cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737–induced apoptosis in bim−/− mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy. •Loss of Bim contributes to adaptive rather than intrinsic bortezomib resistance in multiple myeloma.•A Bim-targeting strategy combining an HDACI with a BH3 mimetic overcomes such resistance through a new link between autophagy and apoptosis.