Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m(2) retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks.
Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer.
Although underpowered, our data suggest that patients with HER2-positive breast cancer overexpressing Hsp90 should be investigated as a "newer" molecular subtype with a significantly higher chance of pCR when receiving anti-Her2 agents.
Novel Hsp90 inhibitor FW-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib.
Thus, our findings show that disrupting Hsp90-Cdc37 interaction may represent a promising strategy against HER2-positive breast cancer, especially those with acquired resistance to trastuzumab.