HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer

• Published in: PloS one Vol. 9; no. 12; p. e115228
• Main Authors: O'Connell, Brenda C, O'Callaghan, Katie, Tillotson, Bonnie, Douglas, Mark, Hafeez, Nafeeza, West, Kip A, Stern, Howard, Ali, Janid A, Changelian, Paul, Fritz, Christian C, Palombella, Vito J, McGovern, Karen, Kutok, Jeffery L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.12.2014; Public Library of Science (PLoS)
• Subjects: Adenomatous polyposis coli; Amino acids; Analysis; Anaphase; Anaphase-promoting complex; Anaphase-Promoting Complex-Cyclosome - metabolism; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apoptosis; Aurora kinase; Benzoquinones - administration & dosage; Benzoquinones - pharmacology; Binding sites; Biochemistry; Biology and Life Sciences; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell culture; Cell cycle; Cell death; Cell division; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Down-Regulation; Drug Synergism; Drugs; Enzyme inhibitors; Heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Humans; Inhibition; Inhibitors; Kinases; Laboratory animals; Lactams, Macrocyclic - administration & dosage; Lactams, Macrocyclic - pharmacology; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Mortality; Non-small cell lung cancer; Non-small cell lung carcinoma; Pharmaceuticals; Phosphorylation; Polo-like kinase 1; Regulators; Research and Analysis Methods; RNA-mediated interference; Small cell lung cancer; Studies; Taxoids - administration & dosage; Taxoids - pharmacology; Treatment Outcome; Tumors; Ubiquitin; Ubiquitin-protein ligase; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115228

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.