PO-502 A potential role for HSP90 in HER2-driven breast cancer (BC)

Abstract

IntroductionHER2 (amplified in 30% of BC) is involved in the activation of many pathways and its function is regulated by HSP90. Thus, HSP90 co-targeting is emerging as a potential molecular target for HER2-directed BC therapy.Material and methodsWe analysed HER2 and HSP90 expression in a panel of BC cell lines, including MCF7 cells stably transfected with a constitutively active HER2. HER2/HSP90 expression and growth inhibition were monitored over time upon exposure to trastuzumab (T) and docetaxel (D), in the presence or absence of HSP90 silencing. We also retrospectively evaluated a series of 24 locally advanced/operable BC patients (pts) who underwent neoadjuvant T+D for HSP90 expression and correlated it with pathological complete response (pCR).Results and discussionsIn the BC cell lines analysed there was no clear-cut correlation between HSP90 and HER2 expression. HER2 transfection into MCF7 cells increased HSP90 mRNA and protein expression; however, treatment with T further increased HSP90 levels. Conversely D increased HER2, but did not affect HSP90, expression. In HER2 +BC cell lines, simultaneous T+D combination resulted in synergistic growth inhibition in vitro, while their staggered combination, particularly T followed by D, did not afford synergistic effects. Effects of simultaneous and staggered treatments on HSP90 and HER2 expression were analysed by WB: HER2 expression decreased in the simultaneous and staggered combination (D followed by T), while HSP90 expression did not change upon combined treatment. The effects of HSP90 silencing and overexepression on functional response to T+D are being analysed in HER2 +BC models: preliminary results indicate that HSP90 silencing in HER2 +BC decreases the therapeutic synergism of the simultaneous T+D combination. Accordingly, in locally advanced/operable pts undergoing neoadjuvant T+D, pCR occurred more frequently in pts with a baseline HSP90 score of 3+, as compared to 2+and 1+ (50.0% vs. 14.3% vs. none, p=0.05). These results suggest the possibility to classify HER2-positive pts into HSP90 defined subgroups and elaborate specific therapeutic strategies.ConclusionPreclinical data indicate that constitutive HER2 activation induces HSP90 expression and HSP90 modulation influences the functional response to combined treatment. Baseline HSP90 expression may potentially represent a pre-requisite of pharmacological response in HER2-addicted BC.