HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells.

Katharina M. Ewers,Jürgen Thomale,Matthias Dobbelstein,Tabea Quilitz,Waltraut Kopp,Shilpa Patil,Xin Wang,Anna Magerhans,Elisabeth Hessmann

doi:10.3390/cancers13246163

Abstract

Simple SummaryPancreatic cancer is currently difficult to treat, but the drug cisplatin represents one of the most important therapeutic options. We find that cells derived from this cancer fall into two classes regarding their sensitivity towards cisplatin, and we observe that cells with high expression levels of GATA6 and microRNA 200 are mostly sensitive. However, those cells that respond poorly to cisplatin can be sensitized by drugs that inhibit HSP90, a protein that helps other proteins to fold properly. This was also found in a mouse model of pancreatic cancer. Our results suggest that the combination of cisplatin with HSP90-inhibitory drugs might improve the treatment of pancreatic cancer.To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most devastating malignancies, with a 5-year survival rate below 5%, raising the need for novel therapies [1]
We first analyzed the response of human cell lines derived from pancreatic ductal adenocarcinoma (PDAC) towards treatment with cisplatin, in parallel and standardized assays
We found that HSP90 inhibitors reduced the levels of Fanconi anemia factors such as FANCA, defining a plausible mechanism of how HSP90 inhibition compromises the repair of platinum-DNA adducts and sensitizes the cells towards cisplatin

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most devastating malignancies, with a 5-year survival rate below 5%, raising the need for novel therapies [1]. Concerning chemotherapy, gemcitabine has long been the mainstay, albeit with limited success; i.e., extending survival by a few months [2]. Platinum-based drugs, such as cisplatin or oxaliplatin, were employed with somewhat better success, at least when compared to gemcitabine, but at the expense of severe side-effects and toxicity [3–5]. The extent of responses strongly varies with either drug, raising the need for reliable predictive markers of therapeutic efficacy. Such biomarkers would help to avoid futile attempts of chemotherapy and to maintain a reasonable balance of therapeutic benefit and drug-induced toxicities

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