Abstract P6-18-13: Identification of optimal combination therapy partners for PI3K/Akt/mTOR pathway inhibitor in triple negative breast cancer

Triple-negative breast cancer (TNBC) is among the most aggressive subtypes, accounts for 10-15% of all breast cancer cases and is characterized by a lack of hormone receptors with a low overall survival rate. Due to the heterogeneity nature of this disease, the absence of validated molecular targets makes it unresponsive to conventional therapies. PI3K/Akt/mTOR pathway is aberrantly activated in TNBC, but single agent therapy is commonly subject to resistance. The goal of this study is to identify the genes that can be targeted to enhance the efficacy of mTOR inhibitor TAK228, an agent that is being investigated as a treatment for advanced solid tumors, in TNBC with PI3K pathway activation. We utilized an in vivo pooled barcoded shRNA library screening to determine the genes that have the potential to be used as TAK228 synthetic lethal partners. Using deep sequencing analysis of the shRNA profiles, we identified several genes whose loss of function conferred synthetic lethality in the presence of TAK228. We found that targeting the candidate genes (WEE1, BMX and MAPK15) with their inhibitors (AZD1775, Ibrutinib and Sunitinib) did not significantly affect the viability, however combination treatment of these agents with TAK228 induced a robust growth inhibition and demonstrated a significant synergy in MDA-MB-468 cell lines. Investigating the activation of relevant survival signaling pathways will further elucidate the mechanism of synthetic lethal interaction. These observations provide a promising rational strategy for the treatment of TNBC with PI3K pathway aberration. Citation Format: Shariati M, Paez-Arango N, Bristow CA, Evans KW, Peoples MD, Carugo A, Heffernan TP, Meric-Bernstam F. Identification of optimal combination therapy partners for PI3K/Akt/mTOR pathway inhibitor in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-13.