title: Ganetespib overcomes resistance to PARP inhibitors in breast cancer by targeting core proteins in the DNA repair machinery.
abstract: DNA damage repair plays essential roles in drug resistance, especially resistance to Poly (ADP-ribose) polymerase (PARP) inhibitors in the clinic. A subset of DNA repair proteins such as Breast cancer gene 1 (BRCA1), BRCA2 and RecA homolog (RAD51) are client proteins of heat shock protein 90 (Hsp90). Clearance of these DNA repair proteins by inhibition of Hsp90 is a promising strategy for overcoming resistance to PARP inhibitors. Here we report the pharmacological analysis of the highly potent second-generation Hsp90 inhibitor, ganetespib. Methods Nuclear BRCA1, BRCA2, and RAD51 expression in breast cancer cells were detected by subcellular fractionation and western blot analysis. Formation of nuclear RAD51 and γ-H2AX foci was analyzed by immunofluorescent staining. The cytotoxicity of ganetespib and ABT-888 in breast cancer cells were evaluated by cell proliferation, colony survival, and apoptosis assay. To investigate the efficacy of this therapy in vivo, SCID mice bearing MCF7 xenografts were treated with ganetespib and ABT-888, both as single agents and in combination. Results Ganetespib significantly destabilized nuclear BRCA1, BRCA2, and RAD51, and efficiently disrupted homologous recombination-mediated DNA double-strand break repair in breast cancer cells. The synergistic antitumor effects of ganetespib and the PARP inhibitor, ABT-888 were observed, and concurrent treatment with both inhibitors synergistically inhibited xenograft tumor growth. Importantly, the combined treatment was well tolerated, without significant loss of body weight or major histological changes in the breast cancer xenograft model. Conclusion These data provide a novel strategy for the treatment of breast cancer with wild type BRCA1 using combination therapy targeting Hsp90 to overcome resistance to PARP inhibitors.
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Juhong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Jinan University, #601 West Huangpu Avenue, Guangzhou, Guangdong, 510632, China.
authors.forename: Yuanzhi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Guangdong Medical University, Dongguang, Guangdong, 523808, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, China.
authors.forename: Daoli
authors.initials: D
authors.lastname: Niu
authors.affiliation: Department of Radiation Oncology, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China. gyblgyy@126.com.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Arkansas College of Medicine, 4301 W. Markham, Slot 771, Little Rock, AR, 72205, USA. fxia@uams.edu.
authors.forename: Fen
authors.initials: F
authors.lastname: Xia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004260:DNA Repair; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D016513:Mice, SCID; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D001562:Benzimidazoles; D018841:HSP90 Heat-Shock Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C533237:STA 9090; D014230:Triazoles; C521013:veliparib; D051135:Rad51 Recombinase
keywords: DNA repair; Drug resistance; Hsp90 inhibitor; PARP inhibitor