Abstract 3832: Combination use of natural Hsp90 inhibitors to reverse BRCA1-mediated platinum resistance in triple negative breast cancer

Abstract

Abstract Background: Triple-negative breast cancers (TNBCs) are highly associated with an aggressive clinical course and poor prognosis, largely due to resistance to chemotherapy. Platinum-based therapies act by causing DNA damage, which in the absence of a functional DNA repair system, leads to cancer cell death. BRCA1, a well-studied tumor suppressor, is critical for repairing DNA damage by homologous recombination. This ability makes BRCA1 an attractive therapeutic target for the re-sensitization of cancer cells to platinum chemotherapies. Recently, we have demonstrated that the chaperone protein heat shock protein 90 (HSP90) is required for BRCA1 stability. While targeted elimination of HSP90s results in a loss of BRCA1, current pharmacological inhibitors also exhibit toxicity unrelated to HSP90. We have found that the natural compounds gedunin, triptolide, and celastrol can modulate HSP90 expression without negative side effects. We believe that combinatory use of these non-toxic compounds can further reduce BRCA1 expression beyond their individual effect to overcome BRCA1-mediated resistance to platinum-based chemotherapies. Study Design: The goal of these experiments is to identify a combination of gedunin, celastrol, and triptolide to maximize BRCA1 degradation (via inhibition of HSP90), impairing the DNA repair system, and allowing carboplatin to effectively eradicate TNBC cells. Using in vitro techniques we will identify the most potent combination of gedunin, celastrol and triptolide to maximize BRCA1 degradation. We will then confirm that this is a HSP90 mediate event that results in the impairment of DNA repair. Using in vivo models of breast cancer we will demonstrate that natural compounds will sensitize BRCA-expressing TNBC cells to carboplatin, inhibiting breast cancer progression and tumor growth. Results: Using Western analysis, we have found that gedunin, celastrol and triptolide each can attenuate HSP90 activity, leading to BRCA1 degradation in BT-20 and MDA-MB-231 TNBC cells. Additionally, we have observed that gedunin, celastrol, and triptolide can each prevent formation of radiation-induced DNA repair complex, as evident by γ-H2AX staining, in HCC1937BRCA1 TNBC cells. Once we identify the most potent combination of our natural compounds, TNBC xenografts with be created and treated with the combination and carboplatin to demonstrate sensitivity to platinum treatment and inhibition of breast cancer progression. Significance: In order to increase survival rates in TNBC patients, it is essential that resistance to chemotherapy be overcome. Successful completion of these studies demonstrating that natural compounds can act as HSP90 inhibitors to reverse platinum resistance without added toxicity would facilitate their rapid incorporation into clinical trials and provide a critically needed therapy for women with TNBC. Citation Format: Kelli E. Valdez, Prabhu Ramamoorthy, Shrikant Anant, Roy Jensen. Combination use of natural Hsp90 inhibitors to reverse BRCA1-mediated platinum resistance in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3832.