Abstract
Abstract Notch signaling affects multiple cellular processes including stem cell maintenance, differentiation, proliferation, motility and survival. Activated NOTCH signaling and up-regulation of tumor-promoting NOTCH target genes are well documented in human breast cancer. Growing evidence suggest the novel role of NOTCH pathway as a survival resistance mechanism against HER2-targeted therapy in the HER2 amplified breast cancer subgroup, accounting for 20% of breast cancers. It was reported that tumor cells that develop intrinsic or acquired resistance to HER2 targeted therapy (at either relapse of the dormant resistant cells or at the progression of HER2 disease), express higher levels of NOTCH pathway genes. The small molecule AL101 is an γ-secretase inhibitor that potently inhibits the activation of all 4 NOTCH receptors (NOTCH1-4). We hypothesize that treatment with AL101, could potentially block activation of this intrinsic resistance mechanism and/or inhibit the acquisition of the acquired resistance. The goal of this study is: (a) to test the efficacy of first line treatment of anti-HER2 drugs combined with AL101, and (b) to test the efficacy of the AL101 as a second line therapy for anti-HER2 resistance breast cancer cells lines. Our study demonstrates the potential utility of HER2-targeted therapy in combination with AL101 as a novel strategy for overcoming the NOTCH signaling induced survival resistance mechanism in HER2 amplified breast cancer cells, and suggests NOTCH inhibitors as potential second-line therapy for recurrent or resistant HER2 amplified breast cancer tumors. Citation Format: Bothaina Nakad, Esther Channah Broner, David Sidransky, Evgeny Izumchenko. Inhibition of NOTCH signaing with g-secretase inhibitor AL101 contributes to overcome resistance against HER2-targeted therapy in HER2 amplified breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-13.
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