4.6 Article

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

期刊

CANCERS
卷 13, 期 24, 页码 -

出版社

MDPI
DOI: 10.3390/cancers13246163

关键词

PDAC; cisplatin; HSP90 inhibition; synergism; platinum-DNA adducts; basal-like subtype

类别

资金

  1. Deutsche Forschungsgemeinschaft (DFG) [5002/KFO5002]
  2. Wilhelm Sander Stiftung
  3. Deutsche Krebshilfe

向作者/读者索取更多资源

Pancreatic cancer cells show varied sensitivities to cisplatin, with some being sensitive due to high expression of GATA6 and microRNA 200, while others can be sensitized by inhibiting HSP90. The combination of cisplatin and HSP90 inhibitors has shown promise in improving treatment outcomes for PDAC.
Simple Summary Pancreatic 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据