title: HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer.
abstract: HSP90 inhibitors are currently undergoing clinical evaluation in combination with antimitotic drugs in non-small cell lung cancer (NSCLC), but little is known about the cellular effects of this novel drug combination. Therefore, we investigated the molecular mechanism of action of IPI-504 (retaspimycin HCl), a potent and selective inhibitor of HSP90, in combination with the microtubule targeting agent (MTA) docetaxel, in preclinical models of NSCLC. We identified a subset of NSCLC cell lines in which these drugs act in synergy to enhance cell death. Xenograft models of NSCLC demonstrated tumor growth inhibition, and in some cases, regression in response to combination treatment. Treatment with IPI-504 enhanced the antimitotic effects of docetaxel leading to the hypothesis that the mitotic checkpoint is required for the response to drug combination. Supporting this hypothesis, overriding the checkpoint with an Aurora kinase inhibitor diminished the cell death synergy of IPI-504 and docetaxel. To investigate the molecular basis of synergy, an unbiased stable isotope labeling by amino acids in cell culture (SILAC) proteomic approach was employed. Several mitotic regulators, including components of the ubiquitin ligase, anaphase promoting complex (APC/C), were specifically down-regulated in response to combination treatment. Loss of APC/C by RNAi sensitized cells to docetaxel and enhanced its antimitotic effects. Treatment with a PLK1 inhibitor (BI2536) also sensitized cells to IPI-504, indicating that combination effects may be broadly applicable to other classes of mitotic inhibitors. Our data provide a preclinical rationale for testing the combination of IPI-504 and docetaxel in NSCLC.
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Brenda C
authors.initials: BC
authors.lastname: O'Connell
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Katie
authors.initials: K
authors.lastname: O'Callaghan
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Tillotson
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Douglas
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Nafeeza
authors.initials: N
authors.lastname: Hafeez
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Kip A
authors.initials: KA
authors.lastname: West
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Janid A
authors.initials: JA
authors.lastname: Ali
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Changelian
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Fritz
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA, United States of America.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D016227:Benzoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D015536:Down-Regulation; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D043823:Taxoids; D000077143:Docetaxel; C112765:tanespimycin; D064173:Anaphase-Promoting Complex-Cyclosome