Abstract B36: Targeting BRCA1 through natural HSP90 inhibitors to reverse platinum resistance in TNBC

Background: Triple-negative breast cancers (TNBCs) are highly associated with an aggressive clinical course, resistance to chemotherapy, and poor prognosis compared to other breast cancer subtypes. However, breast cancers arising in BRCA1 mutation carriers appear to be particularly sensitive to platinum-based chemotherapy agents. The tumor suppressor BRCA1 (breast cancer type 1 susceptibility protein) is part of a protein complex that repairs DNA damage by homologous recombination. Recent studies have shown that tumor cells expressing high levels of BRCA1 are resistant to both ionizing radiation (IR) and platinum-based chemotherapy agents, and that ablation of BRCA1 expression can restore sensitivity to these agents. We have demonstrated that the chaperone protein heat shock protein 90 (HSP90) is required for BRCA1 stability. However, established HSP90 inhibitors exhibit a high level of toxicity unrelated to HSP90. Recently, we observed that the natural compounds gedunin and celastrol modulate HSP90 activity without inducing side effects. We believe that combinatory use of these 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 demonstrate that combination treatment with the HSP90 inhibitors gedunin and celastrol will maximize BRCA1 degradation (via inhibition of HSP90), impair the DNA repair system, and allow carboplatin to effec...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research