title: Ridaforolimus improves the anti-tumor activity of dual HER2 blockade in uterine serous carcinoma in vivo models with HER2 gene amplification and PIK3CA mutation.
abstract: Uterine serous carcinomas (USC) harbor simultaneous HER2 (ERBB2) over-expression and gain of function mutations in PIK3CA. These concurrent alterations may uncouple single agent anti-HER2 therapeutic efficacy making inhibition of the mammalian target of rapamycin (mTOR) a promising option to heighten anti-tumor response.
  
  
  
  Both in vitro and in vivo experiments were conducted to assess proliferation, cell death and anti-tumor activity of ridaforolimus, lapatinib and combination lapatinib, trastuzumab (L/T) and ridaforolimus. With institutional approval, NOD/SCID mice bearing xenografts of non-immortalized, HER2 gene amplified cell lines (ARK1, ARK2) with and without PIK3CA gene mutations were divided into four arm cohorts. Ridaforolimus was administered alone and in combination with L/T. Tumor volumes were assessed and posttreatment analysis was performed.
  
  
  
  We observed dose dependent in vitro abrogation of downstream target proteins including phospho-AKT and phospho-S6. In both in vivo models, single agent ridaforolimus impaired xenograft tumor growth. Combination ridaforolimus and L/T, however, further improved the observed anti-tumor activity only in the ARK1 model with the PIK3CA gene mutation (E542K). The addition of mTOR inhibition to dual HER2 blockade added no additional anti-tumor effects in the ARK2 xenografts. Western blot and immunohistochemical analysis of downstream pathway alterations following in vivo treatment revealed dual HER2 blockade with ridaforolimus was necessary to induce apoptosis, decrease proliferation and abrogate phospho-S6 protein expression in the PIK3CA mutated model.
  
  
  
  These pilot data suggest that PIK3CA gene mutation may be an effective biomarker for selecting those HER2 over-expressing USC tumors most likely to benefit from mTOR inhibition.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Hernandez
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chisholm
authors.affiliation: Department of Medicine, Cancer Center, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Darrell
authors.initials: D
authors.lastname: Borger
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States. Electronic address: wgrowdon@partners.org.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D018293:Cystadenoma, Serous / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000068878:Trastuzumab / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D058534:Class I Phosphatidylinositol 3-Kinases; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C515074:ridaforolimus; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C572449:sapanisertib; D000225:Adenine
keywords: HER2; Rapalog; Ridaforolimus; Trastuzumab resistance; Uterine serous carcinoma; mTOR inhibition