Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenströms Macroglobulinemia

Laubach, Jacob P.; Mitsiades, Constantine S.; Roccaro, Aldo M.; Ghobrial, Irène M.; Anderson, Kenneth C.; Richardson, Paul G.

doi:10.1080/10428190902866732

Cited by 31 publications

(26 citation statements)

References 59 publications

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“…1 However, not all patients with MM respond to BTZ, and most of those who do respond ultimately relapse. 1,47 These findings have stressed the importance of understanding the mechanisms underlying BTZ resistance and the identification of agents that are effective against relapsed/refractory disease. Studies of BTZ-resistant MM cell lines have demonstrated increased secretion of IGF-1 and activation of IGF-1R.…”

Section: Discussionmentioning

confidence: 99%

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Kufe

Avigan

et al. 2014

Blood

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• Targeting the MUC1-C oncoprotein in MM cells potentiates BTZ-induced downregulation of TIGAR and thereby ROS-mediated death.• Targeting MUC1-C is effective in resensitizing BTZ-resistant MM cells to BTZ and thus represents a potential strategy for combination treatment.The proteosome inhibitor bortezomib (BTZ) induces endoplasmic reticulum and oxidative stress in multiple myeloma (MM) cells. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in most MM cells, and targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is effective in inducing reactive oxygen species (ROS)-mediated MM cell death. The present results demonstrate that GO-203 and BTZ synergistically downregulate expression of the p53-inducible regulator of glycolysis and apoptosis (TIGAR), which promotes shunting of glucose-6-phosphate into the pentose phosphate pathway to generate reduced glutathione (GSH). In turn, GO-203 blocks BTZ-induced increases in GSH and results in synergistic increases in ROS and MM cell death. The results also demonstrate that GO-203 is effective against BTZ-resistant MM cells. We show that BTZ resistance is associated with BTZ-induced increases in TIGAR and GSH levels, and that GO-203 resensitizes BTZ-resistant cells to BTZ treatment by synergistically downregulating TIGAR and GSH. The GO-203/BTZ combination is thus highly effective in killing BTZ-resistant MM cells. These findings support a model in which targeting MUC1-C is synergistic with BTZ in suppressing TIGARmediated regulation of ROS levels and provide an experimental rationale for combining with BTZ in certain settings of BTZ resistance. (Blood. 2014;123(19):2997-3006) IntroductionMultiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized in part by the abnormal synthesis and secretion of monoclonal immunoglobulins or light chains.1 Cellular homeostasis is dependent on the balanced regulation of protein synthesis and degradation, the latter of which is predominantly mediated by the ubiquitin-proteosome pathway.2 Bortezomib (BTZ) is a reversible inhibitor of the proteosome that is effective in inducing apoptosis of MM cells and is active in the treatment of this disease.1 BTZ has improved response rates of MM patients to induction therapy and is being used as consolidation after frontline treatment or transplantation. 1,3 However, intrinsic and acquired resistance to BTZ represent a challenge for the treatment of MM, which remains an incurable disease.1 BTZ has been shown to activate the unfolded protein response (UPR), a pathway induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and associated with increases in reactive oxygen species (ROS). 4,5 In this way, BTZ treatment of MM cells induces expression of CCAAT/enhancer binding protein-homologous protein (CHOP; GADD153), a key transcription factor that participates in cellular responses to ER and oxidative stress. [6][7][8] The mechanistic basis for BTZ activity has also been attributed...

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Section: Discussionmentioning

confidence: 99%

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Kufe

Avigan

et al. 2014

Blood

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“…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][8][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.…”

Section: Introductionmentioning

confidence: 99%

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

Kuhn

Berkova

Jones

et al. 2012

Blood

169

159

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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...

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“…Current therapeutic approaches for MM are not very effective due to development of resistance to drugs such as Bortezomib 34,35 . While the mechanism of resistance development to Bortezomib is not clear, it was suggested that MM progenitor cells that are CD138 À and XBP1s À are relatively resistant to Bortezomib 39,40 .…”

Section: Discussionmentioning

confidence: 99%

“…However, development of resistance to Bortezomib has been a major problem in MM therapy 34,35 . Thus, it is necessary to identify novel molecular targets that are necessary for the survival of both parental and Bortezomib resistant MM cells.…”

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confidence: 99%

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

et al. 2015

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Although transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival. Importantly, RelB is constitutively phosphorylated in MM and ERK1 is a RelB kinase. Phospho-RelB remains largely nuclear and is essential for Bim repression. Thus, ERK1-dependent regulation of nuclear RelB is critical for MM survival and explains the NIK-independent role of RelB in MM.

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Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenströms Macroglobulinemia

Cited by 31 publications

References 59 publications

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

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

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

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