PMID- 27765027 OWN - NLM STAT- MEDLINE DCOM- 20170926 LR - 20211204 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 16 IP - 1 DP - 2016 Oct 20 TI - Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. PG - 814 LID - 814 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 (ERalpha) 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. FAU - Becker, Marc A AU - Becker MA AD - Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. becke344@gmail.com. AD - Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA. becke344@gmail.com. FAU - Hou, Xiaonan AU - Hou X AD - Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. FAU - Tienchaianada, Piyawan AU - Tienchaianada P AD - Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. AD - Oncology unit, Department of Medicine, Rajavithi Hospital, Bangkok, 10400, Thailand. FAU - Haines, Brian B AU - Haines BB AD - Molecular Oncology, Merck Research Laboratories, Boston, MA, 02115, USA. FAU - Harrington, Sean C AU - Harrington SC AD - Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. FAU - Weroha, S John AU - Weroha SJ AD - Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. FAU - Sathyanarayanan, Sriram AU - Sathyanarayanan S AD - Molecular Oncology, Merck Research Laboratories, Boston, MA, 02115, USA. FAU - Haluska, Paul AU - Haluska P AD - Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. LA - eng GR - P50 CA116201/CA/NCI NIH HHS/United States GR - T32 DK007352/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20161020 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, CD) RN - 0 (RNA, Messenger) RN - 48Z35KB15K (ridaforolimus) RN - 6YI1L648RH (dalotuzumab) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (INSR protein, human) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Antibodies, Monoclonal/*pharmacology MH - Antibodies, Monoclonal, Humanized MH - Antigens, CD/metabolism MH - Antineoplastic Combined Chemotherapy Protocols MH - Apoptosis/drug effects MH - Blotting, Western MH - Breast Neoplasms/*drug therapy/metabolism/pathology MH - Cell Proliferation/drug effects MH - *Drug Synergism MH - Female MH - Humans MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Neoplasms, Hormone-Dependent/*drug therapy/metabolism/pathology MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA, Messenger/genetics MH - Real-Time Polymerase Chain Reaction MH - Receptor, IGF Type 1/antagonists & inhibitors MH - Receptor, Insulin/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction MH - Sirolimus/*analogs & derivatives/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays PMC - PMC5073873 OTO - NOTNLM OT - Aromatase inhibitors/therapeutic use OT - Breast neoplasms/drug therapy OT - Disease models, Animal OT - Drug resistance, Neoplasm OT - Receptor, IGF type 1 OT - Receptor, Insulin OT - mTOR inhibitor EDAT- 2016/10/22 06:00 MHDA- 2017/09/28 06:00 PMCR- 2016/10/20 CRDT- 2016/10/22 06:00 PHST- 2015/06/29 00:00 [received] PHST- 2016/10/07 00:00 [accepted] PHST- 2016/10/22 06:00 [pubmed] PHST- 2017/09/28 06:00 [medline] PHST- 2016/10/22 06:00 [entrez] PHST- 2016/10/20 00:00 [pmc-release] AID - 10.1186/s12885-016-2847-3 [pii] AID - 2847 [pii] AID - 10.1186/s12885-016-2847-3 [doi] PST - epublish SO - BMC Cancer. 2016 Oct 20;16(1):814. doi: 10.1186/s12885-016-2847-3.