Targeting HSF1 sensitizes cancer cells to HSP90 inhibition

// Yaoyu Chen 1,* , Jinyun Chen 1,* , Alice Loo1 , Savina Jaeger 1 , Linda Bagdasarian 2 , Jianjun Yu 3 , Franklin Chung 1 , Joshua Korn 1 , David Ruddy 2 , Ribo Guo 1 , Margaret E. Mclaughlin 2 , FeiFeng 1 , Ping Zhu 1 , Frank Stegmeier 1 , Raymond Pagliarini 1 , Dale Porter 1 and Wenlai Zhou 1 1 Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA 2 Oncology Translational Research, Novartis Institutes for Biomedical Research, Cambridge, MA, USA 3 Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA, USA * These authors contributed equally to this work. Correspondence: Wenlai Zhou, email: // Keywords : HSF1, cancer cells, HSP90 inhibitor, Melanoma, HCC, DEDD2. Received : April 19, 2013 Accepted : April 21, 2013 Published : April 23, 2013 Abstract The molecular chaperone heat shock protein 90 ( HSP90) facilitates the appropriate folding of various oncogenic proteins and is necessary for the survival of some cancer cells. HSP90is therefore an attractive drug target, but the efficacy of HSP90 inhibitormay be limited by HSP90inhibition induced feedback mechanisms. Through pooled RNA interference screens, we identified that heat shock factor1( HSF1) is a sensitizer of HSP90 inhibitor. A striking combinational effect was observed when HSF1knockdown plus with HSP90 inhibitorstreatment in various cancer cell lines and tumor mouse models. Interestingly, HSF1is highly expressed in hepatocellular carcinoma (HCC) patient samples and HCC is sensitive to combinational treatment, indicating a potential indication for the combinational treatment. To understand the mechanism of the combinational effect, we identified that a HSF1-target gene DEDD2 is involved in attenuating the effect of HSP90 inhibitors. Thus, the transcriptional activities of HSF1induced by HSP90 inhibitorsprovide a feedback mechanism of limiting the HSP90inhibitor’s activity, and targeting HSF1may provide a new avenue to enhance HSP90 inhibitorsactivity in human cancers.