Heat Shock Protein 90: Key Player in New Ovarian Cancer Research
Posted: Friday, January 3, 2020
To date, the treatment of high-grade serous ovarian carcinoma with pharmacologic PARP inhibition seems to work best when cells have defects in DNA damage repair (DDR) mechanisms, such as alterations in expression or function of DNA repair and homologous recombination (HR) genes and proteins, including BRCA1 and BRCA2. Consequently, Denise C. Connolly, PhD, of Fox Chase Cancer Center in Philadelphia, and colleagues worked to make the cells of HR-proficient patients chemically resemble those of HR-deficient ones, for the purpose of treatment with PARP inhibitors. Their results were published in Cancer Biology & Therapy.
Because heat shock protein 90 (HSP90) mediates the maturation and stability of several key proteins required for DNA damage repair, the team explained, a way to “fake” a defect in the repair mechanism would be to destabilize HSP90. They did this with a small-molecule inhibitor of HSP90, ganetespib, consequently disrupting the DNA repair induced by gamma irradiation.
To further demonstrate that ganetespib could sensitize high-grade serous ovarian carcinoma cells lacking “BRCAness” to PARP inhibition, Dr. Connolly and her co-researchers studied how the combination of ganetespib and the PARP inhibitor talazoparib affected the cell viability of these cancers. Among the non–BRCA-mutant cell lines analyzed, the combination was synergistic in OVCAR-3, OC-1, and OC-16.
“From a clinical perspective, these study findings suggest that HSP90 inhibition has the potential to sensitize some patients with high-grade serous ovarian carcinoma who do not have HR pathway alterations to PARP inhibition, and potentially other DNA-damage–inducing agents,” concluded the investigators.
Disclosure: For full disclosures of the study authors, visit tandfonline.com.