Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma

Abstract

Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no ␤5 subunit mutations. Instead, up-regulation of the insulinlike growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNAmediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic. (Blood. 2012;120(16):3260-3270) IntroductionMultiple myeloma is a malignancy of immunoglobulin-secreting clonal plasma cells that is most often found in the bone marrow. 1,2 Modulation of the activity of the ubiquitin-proteasome pathway with the small molecule proteasome inhibitor bortezomib (VEL-CADE) has been validated as a rational therapeutic strategy for this disease 3,4 both in the front-line and relapsed/refractory settings. Despite these and other advances, myeloma remains an incurable disease characterized by decreasing response durations with each subsequent salvage therapy. 5 This is mediated in part through both intrinsic and acquired drug resistance, the latter of which emerges during and after bortezomib therapy. 6 Response rates in patients with previously bortezomib-sensitive disease are typically decreased on drug rechallenge 7-9 and may be as low as 23% among patients who had achieved at least a partial remission previously. 7 These findings indicate a need for an understanding of the molecular basis for bortezomib resistance.Proteasome inhibition acutely activates multiple inducible chemoresistance pathways that reduce the efficacy of bortezomib. One example is the antiapoptotic Akt pathway that can be activated by proteasome inhibitors, 10 and suppression of this pathway can induce chemosensitization to bortezomib. [11][12][13] Another possible mechanism aiding in acquired resistance to bortezomib may be the development of mutations in the bortezomib-binding pocket of the ␤5 proteasome subunit, or increased expression of ␤5 itself. [14][15][16] However, ␤5 proteasome sub...

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

“…Acquisition of bortezomib resistance has been attributed to different mechanisms including increased growth factor expression, 11 a mutated proteasome subunit PSMb5 and overexpression of PSMb5 protein, 5 an upregulated NF-kb signaling pathway, 12,13 and overexpressed antioxidant molecules.…”

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

“…This finding is further supported by the clinical observation that approximately half of initially bortezomib-sensitive MM patients are no longer able to respond to bortezomib once relapsed. 11 This sub-clonal bortezomib-resistance has been attributed to a range of mechanisms; including enhanced growth factor expression, 12 mutated proteasome subunits, 13 deregulated plasma cell maturation markers, 14 and nuclear factor-kappa B (NF-kB) pathway 'addiction' 15 [for a more in-depth exploration of this topic see Murray et al 2014 16 ]. Furthermore, pro-survival NF-kB signaling pathway members were also found to have a broader than anticipated profile in MM whole genome sequencing data.…”

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

“…HEK-293T cells were cultured in DMEM high glucose medium (Cellgro) supplemented with 10% FBS (Sigma), 1% Pen Strep (Gibco) and 1% L-Glutamine (Gibco). Bortezomib-resistant RPMI-8226 cells were generated and maintained as described 61 .…”