Abstract B29: Characterization of the regulatory feedback program components after HER2 inhibition in breast cancer cells

Abstract

Abstract HER2 overexpression drives tumorigenesis in a subset of breast cancers and pharmacological inhibition of this receptor tyrosine kinase is currently used in the clinic for these patients. While all of the cancer cells within the tumor are dependent on HER2 signaling, treatment with HER2 inhibitors results in the establishment of two separate populations; cells that undergo apoptosis and cells that survive. The mechanisms underlying the decision-making processes are not well understood. A proposed mechanism for establishing resistance within a population involves induction of signaling components that may allow for bypass of HER2. Induction of these genes is dependent on AKT inhibition and subsequent activation of the FOXO family of transcription factors. The best-studied adaptive signaling components relevant to HER2-positive breast cancer are HER3, IGF1R, and IR. The involvement of these signaling components in acute adaptive resistance to HER2 inhibition was studied in the HER2-positive BT474 cell line. Lapatinib increased HER3 protein levels in a concentration dependent manner, however, at higher concentrations this effect was reversed. In contrast, inhibition of PI3K increased HER3 levels even at higher concentrations. Time course analysis of HER3 induction demonstrated strong regulation of protein levels at 8 hours post addition of inhibitor. Ongoing work is focused on determining whether these findings are generally applicable to the adaptive gene response. The results reported here provide a framework to model the effects of HER2 inhibition on apoptosis and survival in breast cancer cells. Citation Format: Nareeza Sakur, Marc Fink. Characterization of the regulatory feedback program components after HER2 inhibition in breast cancer cells. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B29.