Exploiting subtype-specific HSP90 targeting for sensitization of PDAC cells towards platinum-based therapy

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This project examines the subtype-specific responsiveness of pancreatic ductal adenocarcinoma (PDAC) towards a combination of platinum treatment and HSP90 inhibition. The rationale behind this combination is based on the central role of the Fanconi anemia pathway in the repair of platinum-driven interstrand crosslinks of DNA. Several members of this pathway are clients of heat shock protein 90 (HSP90), i.e. they depend on the chaperone function of HSP90. When HSP90 is inhibited by small compounds, Fanconi anemia proteins are rapidly degraded. This constitutes a severe defect in the repair of platinum-induced DNA lesions, resulting in extensive chromosome fragmentation and cell death. Preliminary work established the synergy of the two drugs in eliminating PDAC cells, but we also observed considerable variation in drug efficacy and synergy when treating cells from different PDAC patients. We will now investigate the mechanistic and functional consequences of this synergism in DNA repair, cell cycle control and chromosome fragmentation. PDAC susceptibility towards combined platinum therapy and HSP90 inhibition will be evaluated in a variety of PDAC-derived cells with subtype-specific characteristics, and compared to clinical features of the donor patients. The impact of HSP90 inhibition on the response to platinum treatment will also be evaluated in animal models of PDAC, using genetically engineered, orthotopic models.