ABSTRACT
Pharmacological inhibition of PARP is a promising approach in treating high grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) are most active in patients with defects in DNA damage repair (DDR) mechanisms, such as alterations in expression/function of DNA repair and homologous recombination (HR) genes/proteins, including BRCA1 and BRCA2. Benefit of PARPi could be extended towards HR-proficient patients by combining PARPi with agents that functionally abrogate HR. An attractive molecular target for this purpose is heat shock protein 90 (HSP90), which mediates the maturation and stability of several key proteins required for DDR. Here, we tested the hypothesis that targeted inhibition of HSP90 with a small-molecule inhibitor ganetespib would sensitize non-BRCA mutant ovarian carcinoma (OC) cells to PARP inhibition by talazoparib. We used commercially available cell lines, along with several novel HGSOC OC cell lines established in our laboratory. Ganetespib treatment destabilized HSP90 client proteins involved in DNA damage response and cell cycle checkpoint, and disrupted γ-irradiation-induced DNA repair. The effects of the combination of ganetespib and talazoparib on OC cell viability and survival were also analyzed, and among the non-BRCA mutant cell lines analyzed, the combination was synergistic in several cell lines (OVCAR-3, OC-1, OC-16). Together, our data suggest that ganetespib-mediated inhibition of HSP90 effectively disrupts critical DDR pathway proteins and may sensitize OC cells without 'BRCAness' to PARPi. From a clinical perspective, this suggests that HSP90 inhibition has the potential to sensitize some HGSOC patients without HR pathway alterations to PARPi, and potentially other DNA-damage inducing agents.
Subject(s)
DNA Damage , Drug Resistance, Neoplasm , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , DNA Damage/drug effects , DNA Damage/radiation effects , DNA Repair/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Female , HSP90 Heat-Shock Proteins/genetics , Homologous Recombination , Humans , Immunohistochemistry , Mice , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Phthalazines/pharmacology , Radiation, Ionizing , Xenograft Model Antitumor AssaysABSTRACT
For decades, public health advocates have confronted industry over dietary policy, their debates focusing on how to address evidentiary uncertainty. In 1977, enough consensus existed among epidemiologists that the Senate Select Committee on Nutrition and Human Need used the diet-heart association to perform an extraordinary act: advocate dietary goals for a healthier diet. During its hearings, the meat industry tested that consensus. In one year, the committee produced two editions of its Dietary Goals for the United States, the second containing a conciliatory statement about coronary heart disease and meat consumption. Critics have characterized the revision as a surrender to special interests. But the senators faced issues for which they were professionally unprepared: conflicts within science over the interpretation of data and notions of proof. Ultimately, it was lack of scientific consensus on these factors, not simply political acquiescence, that allowed special interests to secure changes in the guidelines.
