Chen, Yaoyu, Chen, Jinyun, Loo, Alice, Jaeger, Savina, Bagdasarian, Linda, Yu, Jianjun, Chung, Franklin, Korn, Joshua, Ruddy, David, Guo, Ribo, Mclaughlin, Megan, Stegmeier, Frank, Pagliarini, Raymond, Porter, Dale and Zhou, Wenlai (2013) Targeting HSF1 sensitizes cancer cells to HSP90 inhibitor. Oncotarget.

Abstract

The molecular chaperone heat shock protein 90 (HSP90) facilitates the appropriate folding of oncoprotein and is hence thought to be necessary for the survival of certain oncogene-driven cancer cells. This specific hypothesis is being tested in clinical trials involving a number of distinct LWM HSP90 inhibitors including NVP-AUY922 and NVP-HSP990. Signs of clinical activity have been observed, most notably in trastuzumab-refractory, HER2-positive breast cancer, in EGFR-driven lung adenocarcinoma and in ALK-driven lung cancer. Through a pooled RNA interference screen, we showed that heat shock factor 1 (HSF1) is the top sensitizer of HSP90 inhibitor and knockdown of HSF1 specifically enhanced cell death induced by the HSP90 inhibitor. A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in a various cell lines and tumor mouse models. In particularly, HSF1 is highly expressed in hepatocellular carcinoma (HCC) patient samples and knockdown of HSF1 sensitizes HSP90 inhibitor in liver cancer model, which might be a new indication for the combinational treatment. To understand the mechanism of the combinational effect, we identified a novel HSF1-target gene DEDD2, which is also involved in attenuation of the activity of HSP90 inhibitors. Interestingly, high expression of DEDD2 is associated with poor prognosis of breast cancer. Thus, the transcriptional activities of HSF1 induced by HSP90 inhibitors suggest a feedback mechanism to attenuate the HSP90 inhibitor activity and targeting HSF1 may provide a new avenue to enhance HSP90 inhibitor efficacy in human cancer, such as HCC.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9503