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

Marc A. Becker, Xiaonan Hou, Piyawan Tienchaianada, Brian B. Haines, Sean C. Harrington, Saravut (John) Weroha, Sriram Sathyanarayanan, Paul Haluska

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article number814
JournalBMC Cancer
Volume16
Issue number1
DOIs
StatePublished - Oct 20 2016

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Somatomedins
Linear Energy Transfer
Hormones
Estrogen Receptor alpha
Breast Neoplasms
Sirolimus
Insulin Receptor Substrate Proteins
letrozole
Phosphorylation
Somatomedin Receptors
Therapeutics
Aromatase Inhibitors
Aromatase
Insulin Receptor
Receptor Protein-Tyrosine Kinases
Growth
Heterografts
Serine
Neoplasms
Protein Isoforms

Keywords

  • Aromatase inhibitors/therapeutic use
  • Breast neoplasms/drug therapy
  • Disease models, Animal
  • Drug resistance, Neoplasm
  • MTOR inhibitor
  • Receptor, IGF type 1
  • Receptor, Insulin

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Becker, M. A., Hou, X., Tienchaianada, P., Haines, B. B., Harrington, S. C., Weroha, S. J., ... Haluska, P. (2016). Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. BMC Cancer, 16(1), [814]. https://doi.org/10.1186/s12885-016-2847-3

Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. / Becker, Marc A.; Hou, Xiaonan; Tienchaianada, Piyawan; Haines, Brian B.; Harrington, Sean C.; Weroha, Saravut (John); Sathyanarayanan, Sriram; Haluska, Paul.

In: BMC Cancer, Vol. 16, No. 1, 814, 20.10.2016.

Research output: Contribution to journalArticle

Becker, MA, Hou, X, Tienchaianada, P, Haines, BB, Harrington, SC, Weroha, SJ, Sathyanarayanan, S & Haluska, P 2016, 'Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer', BMC Cancer, vol. 16, no. 1, 814. https://doi.org/10.1186/s12885-016-2847-3
Becker, Marc A. ; Hou, Xiaonan ; Tienchaianada, Piyawan ; Haines, Brian B. ; Harrington, Sean C. ; Weroha, Saravut (John) ; Sathyanarayanan, Sriram ; Haluska, Paul. / Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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AU - Becker, Marc A.

AU - Hou, Xiaonan

AU - Tienchaianada, Piyawan

AU - Haines, Brian B.

AU - Harrington, Sean C.

AU - Weroha, Saravut (John)

AU - Sathyanarayanan, Sriram

AU - Haluska, Paul

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N2 - 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.

AB - 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.

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KW - Drug resistance, Neoplasm

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KW - Receptor, IGF type 1

KW - Receptor, Insulin

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