title: Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts.
abstract: Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition. However, treatment with nanomolar levels of mTOR inhibitor renders these cells as sensitive to MEK inhibition as a melanoma cell line with mutant BRAF. Similar results were observed in B-Raf wild-type melanoma cells as well as in vivo, where treatment of canine AS tumorgrafts with MEK and mTOR inhibitors was more effective than monotherapy. Our data show that a low dose of an mTOR inhibitor can dramatically enhance angiosarcoma and melanoma response to MEK inhibition, potentially widening the field of applications for MEK-targeted therapy.
authors.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Andersen
authors.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Elissa B
authors.initials: EB
authors.lastname: Boguslawski
authors.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Cynthia Y
authors.initials: CY
authors.lastname: Kuk
authors.affiliation: Frederik Meijer Heart and Vascular Institute, Spectrum Health Hospital, Grand Rapids, MI 49503, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Chambers
authors.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Duesbery
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006394:Hemangiosarcoma / Q000188:drug therapy*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; C506614:mirdametinib; D004159:Diphenylamine; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020123:Sirolimus