Abstract 639: Inhibition of HER2 signaling using targeted therapeutics in breast cancer cell lines

Abstract

Abstract ERBB2/HER2 amplification occurs in 20-30% of all breast cancers and is associated with an aggressive clinical behavior. Therapeutics that target HER2 offer a modest survival benefit when given as monotherapy. Recent studies indicate that in the case of the HER2/EGFR inhibitor lapatinib, there is an initial down-regulation of the PI3K-AKT signaling pathway followed by reactivation of the pathway through p-HER3. Inhibition with much higher doses of lapatinib in vitro prevents the reactivation of the pathway, implying that more effective inhibition of HER2 could lead to more durable responses. To explore this phenomenon more fully, we examined response to lapatinib in a panel of 22 HER2 amplified breast cancer cell lines. Of the 22, there were 5 that were resistant to lapatinib, failing to reach 50% growth inhibition (GI50) even at doses as high as 5 uM. These lines have also been reported to be resistant to trastuzumab. However, all the cell lines in the panel were sensitive to BIBW-2992, which is an irreversible EGFR/ERBB2 inhibitor, with GI50 values in the nanomolar range. Initial western blot analysis indicated that in response to BIBW-2992, there was down-regulation of p-AKT and p-HER3, but that there was recovery of both over time to levels that were comparable to untreated cells. Finally, we observed strong synergistic interactions between BIBW-2992 in combination with a PI3K inhibitor in almost every HER2+cell line tested. These results suggest that even in the setting of resistance to lapatinib and trastuzumab, all HER2 amplified cell lines in our panel are still addicted to HER2 signaling, and that more efficient inhibition of HER2 can result in significant inhibition of growth and loss of viability in HER2 positive breast cancer cell lines. BIBW-2992 was effective against HER2 amplified cells even though inhibition of p-AKT and p-HER3 was not complete. However, addition of PI3K pathway inhibitors resulted in strong synergism in combination with BIBW-2992. These studies set the stage for clinical investigations into the efficacy of such irreversible HER2 inhibitors in patients with HER2 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 639. doi:10.1158/1538-7445.AM2011-639