title: Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition.
abstract: The triple-negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with PARP inhibition in breast cancer cells that harbor silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACi) are a class of drugs that mediate epigenetic changes in expression of HR pathway genes. Here, we compare the activity of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA), and the HDAC1/2-specific inhibitor romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that two of the HDACis tested, SAHA and ROMI, but not VPA, indeed inhibit HR repair and that RAD51, BARD1, and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared with mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting.
authors: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. adrian.wiegmans@qimrberghofer.edu.au.
authors: Adrian P
authors: AP
authors: Wiegmans
authors: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Pei-Yi
authors: PY
authors: Yap
authors: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Ambber
authors: A
authors: Ward
authors: Translational Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Yi Chieh
authors: YC
authors: Lim
authors: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Kum Kum
authors: KK
authors: Khanna
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000235:genetics; D047630:Depsipeptides / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D059767:Recombinational DNA Repair; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001562:Benzimidazoles; D047630:Depsipeptides; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D006877:Hydroxamic Acids; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; C521013:veliparib; D000077337:Vorinostat; D014635:Valproic Acid; C087123:romidepsin; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D045643:DNA Repair Enzymes