Targeting HSF1 sensitizes cancer cells to HSP90 inhibition

// Yaoyu Chen 1,* , Jinyun Chen 1,* , Alice Loo 1 , 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 , Fei Feng 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. HSP90 is therefore an attractive drug target, but the efficacy of HSP90 inhibitor may be limited by HSP90 inhibition induced feedback mechanisms. Through pooled RNA interference screens, we identified that heat shock factor 1( HSF1 ) is a sensitizer of HSP90 inhibitor. A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in various cancer cell lines and tumor mouse models. Interestingly, HSF1 is 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 HSF1 induced by HSP90 inhibitors provide a feedback mechanism of limiting the HSP90 inhibitor’s activity, and targeting HSF1 may provide a new avenue to enhance HSP90 inhibitors activity in human cancers.