Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model

Abstract

Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma.

The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma

“…Notably, ATRA consistently reduced levels of both NRF2 and POMP in bortezomib-naive and -resistant cells either alone or in combination with bortezomib. Our finding of increased activation of NRF2 is consistent with the data of Stessman et al (45), who found in mouse and human cell line models of myeloma that bortezomib resistance produced a gene signature enriched for downstream targets of this transcription factor, although they did not look at what downstream NRF2 effectors could be involved.…”

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

“…The second-generation proteasome inhibitors carfilzomib (CFZ) (2), ixazomib (3), and marizomib (4) also are showing improved pharmacological properties and promising responses. Nonetheless, MM cells develop resistance to BTZ, leading to relapse of disease in most patients (5,6).…”

Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors

“…While several prior studies have demonstrated synergism between proteasome and HDAC inhibitors, [35][36][37][38][39][40] the utility of such combinations in models of acquired resistance to proteasome inhibitors is largely unknown. We also demonstrated the generality of this approach for achieving synergism, as different combinations of carfilzomib or oprozomib with vorinostat or entinostat were all effective.…”

“…Several reports have shown that proteasome inhibitors and HDAC inhibitors synergize to overcome intrinsic resistance, [35][36][37][38][39] though considerably less is known about this potential synergy in models of acquired resistance to proteasome inhibitors. 40 Synergy between bortezomib and STAT3 inhibitors has also been reported. 41 Bortezomib, as well as carfilzomib and oprozomib, also induce expression of antiapoptotic Mcl-1, and the activities of these agents can be enhanced by suppression of Mcl-1 expression or inhibition of Mcl-1 using obatoclax (GX15-070).…”