ArticleInvestigational new drugs2017
Ganetespib overcomes resistance to PARP inhibitors in breast cancer by targeting core proteins in the DNA repair machinery.
Article in Investigational new drugs, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 32 citations in OpenAlex.
- HSP90 shields ROC1/RBX1 from proteasomal degradation by CHIP E3 ubiquitin ligase to promote lung adenocarcinoma.Signal transduction and targeted therapy · 2026Article
- Article
- Therapeutic advances and application of PARP inhibitors in breast cancer.Translational oncology · 2025Review
- Curcumin Induces Homologous Recombination Deficiency by BRCA2 Degradation in Breast Cancer and Normal Cells.Cancers · 2025Article
- Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells.Cancer science · 2025Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- DNA Double-Strand Break Repair Inhibitors: YU238259, A12B4C3 and DDRI-18 Overcome the Cisplatin Resistance in Human Ovarian Cancer Cells, but Not under Hypoxia Conditions.Current issues in molecular biology · 2023Article
- Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.NPJ breast cancer · 2022Article
- The Chaperone System in Salivary Glands: Hsp90 Prospects for Differential Diagnosis and Treatment of Malignant Tumors.International journal of molecular sciences · 2022Article
- PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.Expert opinion on investigational drugs · 2022Review
- Ganetespib selectively sensitizes cancer cells for proximal and distal spread-out Bragg peak proton irradiation.Radiation oncology (London, England) · 2022Article
- MYB proto-oncogene like 2 promotes hepatocellular carcinoma growth and glycolysis via binding to theBioengineered · 2022Article
- Understanding and overcoming resistance to PARP inhibitors in cancer therapy.Nature reviews. Clinical oncology · 2021Review
- Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.Cell death & disease · 2021Article
- Small-molecule drug repurposing to target DNA damage repair and response pathways.Seminars in cancer biology · 2021Review
- Cancer drug resistance: rationale for drug delivery systems and targeted inhibition of HSP90 family proteins.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition.Cancer biology & therapy · 2019Article
- Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies.Oncotarget · 2018Review
- Targeting protein quality control pathways in breast cancer.BMC biology · 2017Review
- Drugging the Cancers Addicted to DNA Repair.Journal of the National Cancer Institute · 2017Review
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Authors and funding
11 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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