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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer

Authors: Marc A. Becker, Xiaonan Hou, Piyawan Tienchaianada, Brian B. Haines, Sean C. Harrington, S. John Weroha, Sriram Sathyanarayanan, Paul Haluska

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option.

Methods

Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; “MK-0646”; anti-IGF-1R antibody), ridaforolimus (RIDA; “MK-8669”; mTORC1 small molecule inhibitor) and letrozole (“LET”, aromatase inhibitor).

Results

With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach.

Conclusion

These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors.
Appendix
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Literature
1.
2.
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–74.PubMedPubMedCentral
3.
O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.CrossRefPubMedPubMedCentral
4.
Di Cosimo S, Sathyanarayanan S, Bendell JC, Cervantes A, Stein MN, Brana I, et al. Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial. Clin Cancer Res. 2015;21:49–59.CrossRefPubMed
5.
Timmermans F, Velghe I, Vanwalleghem L, De Smedt M, Van Coppernolle S, Taghon T, et al. Generation of T cells from human embryonic stem cell-derived hematopoietic zones. J Immunol. 2009;182:6879–88.CrossRefPubMed
6.
Zhou DJ, Pompon D, Chen SA. Stable expression of human aromatase complementary DNA in mammalian cells: a useful system for aromatase inhibitor screening. Cancer Res. 1990;50:6949–54.PubMed
7.
8.
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55.CrossRefPubMed
9.
Kern SE, Xie G, White JL, Egan TD. A response surface analysis of propofol-remifentanil pharmacodynamic interaction in volunteers. Anesthesiology. 2004;100:1373–81.CrossRefPubMed
10.
Hou X, Huang F, Macedo LF, Harrington SC, Reeves KA, Greer A, et al. Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer. Cancer Res. 2011;71:7597–607.CrossRefPubMedPubMedCentral
11.
Harrington SC, Weroha SJ, Reynolds C, Suman VJ, Lingle WL, Haluska P. Quantifying insulin receptor isoform expression in FFPE breast tumors. Growth Horm IGF Res. 2012;22:108–15.CrossRefPubMedPubMedCentral
12.
Pollak M. Targeting insulin and insulin-like growth factor signalling in oncology. Curr Opin Pharmacol. 2008;8:384–92.CrossRefPubMed
13.
14.
Robertson JF, Ferrero JM, Bourgeois H, Kennecke H, de Boer RH, Jacot W, et al. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol. 2013;14:228–35.CrossRefPubMed
15.
Becker MA, Hou X, Harrington SC, Weroha SJ, Gonzalez SE, Jacob KA, et al. IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors. Breast Cancer Res. 2012;18:1808–17.
16.
Haluska P, Carboni JM, TenEyck C, Attar RM, Hou X, Yu C, et al. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther. 2008;7:2589–98.CrossRefPubMedPubMedCentral
17.
Fagan DH, Uselman RR, Sachdev D, Yee D. Acquired resistance to tamoxifen is associated with loss of the type I insulin-like growth factor receptor: implications for breast cancer treatment. Cancer Res. 2012;72:3372–80.CrossRefPubMedPubMedCentral
18.
19.
Kim JG, Kang MJ, Yoon YK, Kim HP, Park J, Song SH, et al. Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody. PLoS One. 2012;7:e33322.CrossRefPubMedPubMedCentral
20.
Ulanet DB, Ludwig DL, Kahn CR, Hanahan D. Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc Natl Acad Sci U S A. 2010;107:10791–8.CrossRefPubMedPubMedCentral
21.
Bid HK, Zhan J, Phelps DA, Kurmasheva RT, Houghton PJ. Potent inhibition of angiogenesis by the IGF-1 receptor-targeting antibody SCH717454 is reversed by IGF-2. Mol Cancer Ther. 2012;11:649–59.CrossRefPubMed
22.
Sciacca L, Costantino A, Pandini G, Mineo R, Frasca F, Scalia P, et al. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene. 1999;18:2471–9.CrossRefPubMed
23.
Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002;277:39684–95.CrossRefPubMed
24.
Mathieu MC, Clark GM, Allred DC, Goldfine ID, Vigneri R. Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians. 1997;109:565–71.PubMed
25.
Haluska P, Shaw HM, Batzel GN, Yin D, Molina JR, Molife LR, et al. Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Breast Cancer Res. 2007;13:5834–40.
26.
Ellis MJ, Singer C, Hornby A, Rasmussen A, Cullen KJ. Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res Treat. 1994;31:249–61.CrossRefPubMed
27.
Malaguarnera R, Belfiore A. The insulin receptor: a new target for cancer therapy. Front Endocrinol. 2011;2:93.CrossRef
28.
Becker MA, Ibrahim YH, Cui X, Lee AV, Yee D. The IGF pathway regulates ERalpha through a S6K1-dependent mechanism in breast cancer cells. Mol Endocrinol. 2011;25:516–28.CrossRefPubMedPubMedCentral
Metadata
Title
Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer
Authors
Marc A. Becker
Xiaonan Hou
Piyawan Tienchaianada
Brian B. Haines
Sean C. Harrington
S. John Weroha
Sriram Sathyanarayanan
Paul Haluska
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2847-3

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