Abstract 5438: Resistance to β1 integrin inhibition in HER2 amplified cancers is mediated by HER3

Abstract

Abstract Our previous work focused on investigating β1 integrin as a target for BC, alone and with radiation therapy. It is well recognized that there is significant cross talk between the EGFR family of receptors and β1 integrin signaling, and a relative resistance of HER2+ BC to β1 integrin inhibitory agents. In 2006, we published our findings that β1 integrin inhibition enhanced the effect of trastuzumab in HER2+ BC. Subsequently, others and we reported that β1 integrin inhibition enhanced the cytostatic effect of multiple HER2-targeted therapies in HER2+ BC. However, the nature of cross talk between β1 integrins and HER2, and the role of β1 integrin in HER2+BC resistance remains unknown. In addition, HER2+BCs have higher rates of local recurrence after radiotherapy, consistent with previous work showing relative radioresistance in HER2+BC. The most potent mitogenic HER2 signaling in HER2+BC occurs upon heterodimerization with HER3. We hypothesized that HER3 could mediate significant resistance to β1 integrin targeting in HER2+BC. To test this, we correlated β1 integrin and HER3 expression levels in SKBR3 cells over several time points using WB. Inhibitions of β1 integrin activity or shRNA knockdown of HER3 lead to upregulation of HER3 and β1 integrin, respectively. To test whether HER3 knockdown enhanced β1 integrin inhibition, we estimated proliferation by quantitating Ki-67 expression in SKBR3 cells in response to treatment. β1 integrin inhibition lead to a ∼50% reduction in Ki-67 positive cells (48%-22%), which was further enhanced by 50% with HER3 knockdown (12%), p<0.05. In addition, HER3 knockdown enhanced the cytostatic effect of ionizing radiation (IR) by ∼50% (32% to 14%), p<0.05. Enhanced cytostasis was correlated with a significant down modulation of p-HER2 and p-473 Akt on WB. In conclusion, our data indicate that HER3 plays a role in mediating resistance to β1 integrin inhibition in HER2+BC. Further mechanistic and in vivo validation are on going. Citation Format: Catherine C. Park, Dhara Amin, Hui Zhang, Mark Moasser. Resistance to β1 integrin inhibition in HER2 amplified cancers is mediated by HER3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5438. doi:10.1158/1538-7445.AM2014-5438