HSP90 inhibition in HER2-positive breast cancer cells

Abstract

e14573 Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in survival. We aimed to assess the anti-tumor effect of the HSP90 inhibitor NVP-AUY922 in HER-2 positive breast cancer cell lines. Methods: HER2 positive breast cancer cell lines with varied sensitivity to trastuzumab (Sensitive: BT474, SKBR3; acquired resistance: BT474Res, SKBR3Res; innate resistance: HCC1419, HCC1954, MDA-MB-453) were treated with the HSP90 inhibitor NVP-AUY922 (Novartis) and trastuzumab. IC50s were determined using the acid phosphatase assay. HER2, Akt and HSP90 levels were determined by immunoblotting after treatment with NVP-AUY922. Combinations of NVP-AUY922 with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474 and SKBR3 cells. Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM. Combined treatment with NVP-AUY922 (10 nM) and trastuzumab (10 nM) showed significantly greater inhibition of growth than either trastuzumab or NVP-AUY922 alone in BT474 and BT474Res cell lines (p<0.005). In SKBR3 and SKBR3Res cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone ( Table 1 ). Treatment with NVP-AUY922 resulted in a dose-dependent decrease in HER2 and Akt levels in trastuzumab-sensitive and -resistant cells. Combinations of docetaxel, cisplatin or 5-DFUR with NVP- AUY922 were antagonistic in both BT474 and SKBR3 cells (CI values >1). Conclusions: This study demonstrates that NVP-AUY922 has anti-tumor activity in trastuzumab-sensitive, and in both innate and acquired trastuzumab-resistant HER2 positive breast cancer cells. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of such combinations. However, combinations with other targeted therapies, such as trastuzumab, warrant further investigation. [Table: see text] [Table: see text]