Abstract 613: Increased PI3K/AKT activity, which confers resistance to trastuzumab, can be overcome by lapatinib

Abstract Trastuzumab and lapatinib provide clinical benefit to women with HER2 positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. There are no clinically validated biomarkers of resistance to therapy. We evaluated responses to trastuzumab and lapatinib in a panel of 17 HER2-amplified cell lines in both two and three dimensional culture and investigated the role of receptor tyrosine kinase (RTK) signaling and PI3K/AKT pathway activation in resistance. We also conditioned four cell lines to acquire trastuzumab resistance, and two additional cell lines to acquire lapatinib resistance. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1 and MDA-453 cell lines are innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202 and UACC-893 cells are innately lapatinib resistant. Lapatinib is active in both de novo (SUM-225, HCC-1419 and HCC-1954) and acquired trastuzumab resistant cell lines. Increased phosphorylation of HER2, EGFR, HER3 and IGF-1R correlated with response to lapatinib but not trastuzumab. p95HER2 levels correlated with response to lapatinib, however p95HER2 levels also correlated with levels of full length HER2, indicating that p95HER2 may not be an independent marker of lapatinib response. A decrease in AKT phosphorylation in response to trastuzumab or lapatinib treatment correlated significantly with response to either agent, indicating that loss of pAKT is a biomarker of response to both HER2-targeted therapeutics. Accordingly, trastuzumab treatment of trastuzumab resistant cells had little effect on AKT phosphorylation, whereas treatment of these cells by lapatinib significantly reduced pAKT levels. Thus, lapatinib retains its activity in trastuzumab resistance via continued dephosphorylation of AKT. We also observed that loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab yet lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway confers resistance to trastuzumab which can be overcome by lapatinib. In conclusion, pharmacological targeting of the PI3K/AKT pathway may provide benefit to HER2 positive breast cancer patients who are resistant to trastuzumab therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 613.