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Ganetespib overcomes resistance to PARP inhibitors in breast cancer by targeting core proteins in the DNA repair machinery

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Summary

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.

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Acknowledgements

We thanks Synta Pharmaceuticals (Lexington) for providing Ganetespib (STA-9090).

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Authors and Affiliations

  1. The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China

    Juhong Jiang, Jing Liu, Lin Fu, Ziqing Zhou & Yingying Gu

  2. Department of Pathology, the First Affiliated Hospital, Jinan University, #601 West Huangpu Avenue, Guangzhou, Guangdong, 510632, China

    Yuanzhi Lu

  3. Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Zhi Li

  4. Department of Biochemistry, Guangdong Medical University, Dongguang, Guangdong, 523808, China

    Liping Li

  5. Department of Radiation Oncology, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, China

    Daoli Niu & Wenwei Xu

  6. Arkansas College of Medicine, 4301 W. Markham, Slot 771, Little Rock, AR, 72205, USA

    Fen Xia

Authors
  1. Juhong Jiang
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  2. Yuanzhi Lu
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  3. Zhi Li
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  4. Liping Li
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  5. Daoli Niu
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  6. Wenwei Xu
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  7. Jing Liu
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  8. Lin Fu
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  9. Ziqing Zhou
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  10. Yingying Gu
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  11. Fen Xia
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Corresponding authors

Correspondence to Yingying Gu or Fen Xia.

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The authors declare that they have no conflict of interests.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81272901 to Juhong Jiang and No. 81372298 to Yuanzhi Lu).

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We declare that all experiments were performed in compliance with all laws of China.

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For this type of study, formal consent is not required.

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Juhong Jiang and Yuanzhi Lu contributed equally

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Jiang, J., Lu, Y., Li, Z. et al. Ganetespib overcomes resistance to PARP inhibitors in breast cancer by targeting core proteins in the DNA repair machinery. Invest New Drugs 35, 251–259 (2017). https://doi.org/10.1007/s10637-016-0424-x

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  • DOI: https://doi.org/10.1007/s10637-016-0424-x

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