IGF-1R is overexpressed in poor-prognostic subtypes of multiple myeloma

Chng, Wee Joo; Gualberto, Antonio; Fonseca, Rafaël

doi:10.1038/sj.leu.2403997

Cited by 58 publications

(39 citation statements)

References 7 publications

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“…on May 12, 2018. by guest www.bloodjournal.org From myeloma, 33,34 and this aberrant expression, as well as higher IGF-1 levels themselves, have been related to disease progression, severity, and prognosis. 30,[34][35][36][37] Our current studies revealed evidence that increased IGF-1 signaling through enhanced IGF-1 secretion and IGF-1R activation was associated with the phenotype of resistance to bortezomib (Figure 2). In addition, gene expression profiling confirmed that genes acutely activated by IGF-1 stimulation were chronically expressed in our BR cell lines (Table 2).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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

View full text Add to dashboard Cite

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“…With a small cohort of 37 newly diagnosed patients, Bataille et al have shown that IGF-1R expression on MMCs, detected by fluorescence-activated cell sorter (FACS) analysis, had poor prognosis value. 29 Using a cohort of 72 newly diagnosed patients and IGF-1R expression detected by Affymetrix microarray (Affymetrix, Santa Clara, CA), Chng et al 30 failed to find a prognosis value of IGF-1R expression, whereas IGF-1R expression was increased in poor prognosis groups. The prognostic value of the other MGF receptors was not documented yet.…”

Section: Introductionmentioning

confidence: 99%

The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor

Sprynski

Hose

Caillot

et al. 2009

Blood

152

141

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“…IL-6, another major MM growth factor, has further been shown to act, in part, via recruitment of IGF-1R (25,26). Furthermore, IGF-1R expression is associated with high-risk clinical subtypes that have been shown to have a particularly poor prognosis (27,28,29), in particular t (4;14) and t(14;16) translocation groups (23), and abnormal IGF-1 expression has been linked to progression from monoclonal gammopathy of undetermined significance (MGUS) to MM (30).…”

Section: Introductionmentioning

confidence: 99%

Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134

Liang

Yang

Trieu

et al. 2011

Clinical Cancer Research

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Purpose: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM. Experimental Design: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model. Results: GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 μmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134–induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134–treated mice, impairment of glucose tolerance was modest. Conclusions: These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies. Clin Cancer Res; 17(14); 4693–704. ©2011 AACR.

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IGF-1R is overexpressed in poor-prognostic subtypes of multiple myeloma

Cited by 58 publications

References 7 publications

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

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

The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor

Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134

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