Different Mechanisms for Acquired Resistance to Trastuzumab and Lapatinib in HER2 Positive Breast Cancers: Role of ER and HER2 Reactivation.
Authors: Y. Wang, B. Hennessy, R. McAninch Ward, M. Rimawi, C. Huang, G. Mills, C. Osborne, R. Schiff
Journal: Cancer Research (2009)

Abstract About 25% of human breast cancers are amplified for HER2 with half of these tumors also expressing estrogen receptor (ER). Therapies targeting HER2 are very effective in the metastatic and the adjuvant settings, especially, although de novo or acquired resistance are still major problems. Trastuzumab (T) and lapatinib (L) are approved drugs now used in the clinic for treatment of HER2+ tumors. Data suggest that T works primarily by blocking signals generated by HER2 homodimers, while L is a small molecule tyrosine kinase inhibitor that more completely blocks the pathway by inhibiting HER1 in addition to HER2. In the clinic, these drugs demonstrate incomplete cross-resistance since L is active in some patients with T-resistant tumors. However, the mechanisms for this resistance have not been clarified.To investigate the mechanisms for acquired resistance, we developed a panel of HER2+ cell lines resistant to T, L, and L+T by long-term exposure to increasing drug concentration in vitro. Two of these lines, BT474 and UACC812, are amplified for HER2 and also express ER, and they, together with subclones resistant to L, T, and L+T, were used to better understand potential resistance mechanisms. Western blot analysis of the parental BT474 and its resistant subclones showed that subclones resistant to T had reactivated the HER2 signaling pathway, while subclones resistant to L or L+T in which the HER receptor layer was more completely inhibited showed continued complete blockade of the HER2 pathway at the receptor layer but high levels of ER activity and phosphorylated-AKT. L, but not L+T, subclones after more prolonged time in culture did reactivate the HER pathway. UACC812 resistant cells were similar to BT474: T-resistant clones showed evidence of reactivation of HER signaling while L and L+T resistant clones showed enhanced ER activity. These cells showed no reactivation of HER signaling even after prolonged exposure in vitro. Consistent with these data, both BT474 and UACC812 T-resistant clones were still sensitive to and cell proliferation was inhibited by L. L-resistant clones, however, were also resistant to T. The potent anti-estrogen fulvestrant (F) was used to evaluate the role of ER in these resistant clones. T-resistant clones from both parental lines were resistant to F, indicating that ER had no role in resistance. In contrast, L and L+T-resistant clones, but not parental cells, were extremely sensitive to F with significant inhibition of cell proliferation in vitro.These data demonstrate that only partial inhibition of the HER2 pathway in breast cancer cells by T can be overcome by activating other components of the HER pathway. Resistance to more complete HER2 blockade with L or L+T requires reactivation of a redundant cell survival pathway, in this case ER, which is upregulated by HER2 blockade. Optimal therapy in those tumors may require both ER and HER2-targeted therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 708.