Abstract B42: Heat Shock Protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibition and limits the effectiveness of inhibitors

The receptor for the hepatocyte growth factor (HGF) is encoded by the MET oncogene and its activation results in cell growth, survival, motility and invasiveness. Deregulated HGF/MET signaling is observed in many tumors and both HGF and MET are attractive candidates for targeted therapies. Unexpectedly, we found that in ovarian cancer cells the activation of the MET receptor downmodulated the expression of the small heat shock protein 27 (HSP27), which functions as a molecular chaperone and as an antiapoptotic protein. In MET addicted gastric carcinoma cells, where MET is constitutively active, MET kinase inhibition by JNJ-38877605 up-regulated HSP27 expression. More importantly, in these gastric carcinoma cells suppression of HSP27 was alone able to induce cell death and increased cell susceptibility to MET inhibition. HSP27 suppression did not affect MET stability and phosphorylation, but increased activation of caspase 3, which is a known HSP27 client protein. Regulation of HSP27 expression by MET signaling occurred at transcriptional level, as confirmed by the use of HSP27 promoter in a reporter assay. It was not due to the engagement of HSF1, the master key transcription factor regulating HSPs expression, but depended on MEK activation and resulting HIF 1alpha stabilization. MEK inhibition and HIF 1 alpha silencing resulted in the induction of HSP27, suggesting a direct or indirect transcriptional repression. Altogether data show that MET activation down-regulates and MET inhibition up-regulates HSP27 expression, and that HSP27 increased expression protects cells from death induced by MET inhibitors. Therefore, in therapies with MET targeting agents, HSP27 increase might impair the effectiveness of MET inhibitors. As it is known that HSP27 protects cells for chemotherapeutics, data suggest that HSP27 might strongly affect combinatorial treatments.