Abstract 2553: Inhibition of γ-secretase in combination with Lapatinib induces tumor regression in vivo

Abstract

Amplification, over-expression, and/or hyperactivity of ErbB-2 occur in 15-30% of breast tumors which include both luminal B and the HER2+ subtypes. Metastatic breast tumors that overexpress ErbB-2 are difficult to treat and generally resistant to trastuzumab. Lapatinib, a dual EGFR/ErbB-2 tyrosine kinase inhibitor, is approved for the treatment of ErbB-2-positive breast cancer that has advanced during or after trastuzumab treatment. However, resistance to lapatinib occurs in cell culture models in vitro. We have recently published that overexpression of ErbB-2 suppresses Notch-1 activity and this is reversed by inhibitors of ErbB-2, trastuzumab or a tyrosine kinase inhibitor. Furthermore, we demonstrated that trastuzumab resistance is reversed when Notch-1 is downregulated by siRNA or when cells are treated with a gamma-secretase inhibitor (MRK-003, GSI). Additionally, in an independent study we showed that GSI also prevented resistance to lapatinib. Since lapatinib is a very potent inhibitor of ErbB-2 tyrosine kinase activity in vitro, we asked whether a combination therapy based on lapatinib and GSI can prevent the resistant phenotype by using a pre-clinical in vivo model. BT474 breast tumor xenografts were generated in athymic mice and randomized to vehicle, GSI, lapatinib, or lapatinib plus a GSI. Tumor size was measured up to 13 weeks with treatments. The xenograft studies using BT474 lapatinib sensitive cells demonstrated that lapatinib treatment alone inhibited tumor growth by 40%. GSI alone had no effect on growth of tumors compared to vehicle control. However, GSI plus lapatinib significantly reduced tumor growth where regression was observed. Tumor histology of lapatinib plus GSI-treated tumors displayed a significant decrease in Ki67, a proliferation marker, and an increase in apoptotic cells as measured by TUNEL. Furthermore, both ERK1/2 and AKT1 phosphorylated proteins were undetectable by western blot in tumors treated with lapatinib plus GSI. These results suggest that both ErbB-2 and Notch activities must be inhibited to induce tumor regression of ErbB-2 positive breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2553. doi:10.1158/1538-7445.AM2011-2553

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

“…Invasive breast cancers have a 15%-30% prevalence of HER2 overexpression, and while many women with HER2-positive tumors (gene amplified or protein overexpressed) respond to anti-HER2 therapies in the adjuvant and metastatic settings [40,71], 20% of these patients never respond, and many more acquire resistance to these therapies after an initial response [36,40,45,[72][73][74]. Numerous trastuzumab resistance mechanisms in breast cancer have been reviewed by Pohlmann et al [36].Those that appear most relevant to EnCa include (a) increased expression of a constitutively active p95HER2 truncated variant that signals but does not bind antibody [73,75]; (b) upregulation of downstream activators such as via PIK3CA mutation [76], loss of PTEN function [77,78], or increased AKT and S6K phosphorylation [76,79,80]; and (c) signaling through alternative pathways including other HER family members such as EGFR and HER3 [81][82][83][84] and unrelated pathways such as Notch [85,86]. Significant preclinical and clinical efforts to examine and overcome anti-HER2 therapy resistance in breast cancer have focused on these fundamental areas, and such studies have led to improvements in clinical outcome [87,88].…”