title: Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells.
abstract: There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1.
authors.affiliation: Georgia Regents University, Augusta, GA.
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Ha
authors.affiliation: Houston Methodist Research Institute, Houston, TX; These authors contributed equally to this work.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Houston Methodist Research Institute, Houston, TX; These authors contributed equally to this work.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Choi
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT.
authors.forename: Srividya
authors.initials: S
authors.lastname: Bhaskara
authors.affiliation: Weill Cornell Medical College, New York, NY.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Houston Methodist Research Institute, Houston, TX.
authors.forename: Santhana G T
authors.initials: SG
authors.lastname: Devaraj
authors.affiliation: Houston Methodist Research Institute, Houston, TX.
authors.forename: Bhavin
authors.initials: B
authors.lastname: Shah
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Houston Methodist Research Institute, Houston, TX.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Weill Cornell Medical College, New York, NY.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Vanderbilt University, Nashville, TN.
authors.forename: Scott
authors.initials: S
authors.lastname: Hiebert
authors.affiliation: Houston Methodist Research Institute, Houston, TX.
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D000077767:Panobinostat; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D000077337:Vorinostat; D000077767:Panobinostat; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; D002945:Cisplatin