title: Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. becke344@gmail.com.|Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA. becke344@gmail.com.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Becker
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.|Oncology unit, Department of Medicine, Rajavithi Hospital, Bangkok, 10400, Thailand.
authors.forename: Piyawan
authors.initials: P
authors.lastname: Tienchaianada
authors.affiliation: Molecular Oncology, Merck Research Laboratories, Boston, MA, 02115, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haines
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Harrington
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: S John
authors.initials: SJ
authors.lastname: Weroha
authors.affiliation: Molecular Oncology, Merck Research Laboratories, Boston, MA, 02115, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Sathyanarayanan
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D012333:RNA, Messenger; C515074:ridaforolimus; C569480:dalotuzumab; C546842:MTOR protein, human; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Aromatase inhibitors/therapeutic use; Breast neoplasms/drug therapy; Disease models, Animal; Drug resistance, Neoplasm; Receptor, IGF type 1; Receptor, Insulin; mTOR inhibitor