Combining HSP90 Inhibition with Standard Therapies for HER2 Positive Breast Cancer.

Abstract Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in cell survival. We aimed to assess the anti-tumor effects 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, MDA-MB-361; 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 trastuzumab were tested in BT474, BT474Res, SKBR3, SKBR3Res, HCC1954, and MDA-MB-361 cells. Combinations with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474, SKBR3, HCC1954, MDA-MB-453 and MDA-MB-361 cells.Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM and NVP-AUY922 treatment reduced HER2 and Akt levels in a dose dependent manner. 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, SKBR3Res, HCC1954, MDA-MB-453 and MDA-MB-361 cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone (Table 1). Combinations of docetaxel, cisplatin or 5-DFUR with NVP-AUY922 were antagonistic in all cell lines tested (CI values >1).Conclusions: This study demonstrates that NVP-AUY922 has anti-tumour activity in HER2 positive breast cancers regardless of sensitivity to trastuzumab. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of concurrent administration of NVP-AUY922 with chemotherapy. However, alternative scheduling or combinations with other targeted therapies warrants further investigation.Table 1: Percentage growth in response to NVP-AUY922 and trastuzumab. BT474BT474ResSKBR3SKBR3ResHCC1954MDA-MB-361Trastuzumab53.3 +/- 4.990.4 +/- 7.669.5 +/- 16.179.5 +/- 8.2102.9 +/- 15.558.4 +/- 3.3AUY92255.0 +/- 1.192.6 +/- 11.933.3 +/- 9.719.1 +/- 6.152.2 +/- 13.88.2 +/- 6.2Tras+AUY92222.0 +/- 2.3*59.7 +/- 17.5*30.6 +/- 7.518.3 +/- 4.347.2 +/- 3.42.5 +/- 2.2 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5055.