LAUSR

One in 8 women will develop breast cancer during the course of her life. Recent developments in the field of drug development have provided a significant increase in progression free survival and decrease in mortality of this disease. However, one of the main problems in breast cancer remains the development of resistance to current treatments and relapse of the disease. Moreover, there is no known target for the treatment of the triple negative breast cancers (TNBC) subset, which is more aggressive than the other types of the disease. Therefore, it is imperative to develop new drugs that can block the activity of pro-survival signaling within the cancer cells and inhibit their growth, particularly in the TNBC subset. In an attempt to identify such drugs, we screened a panel of 13 compounds, containing the general structure of 1,5-diheteroarylpenta-1,4-dien-3-one (compounds 34 to 46), for their effectiveness in inhibiting the growth of both TNBC and ER+ breast cancers. The IC50s for these compounds were in the range of 63 to 8346 nM against various breast cancer cell lines. Interestingly, the most potent compound (# 34), (1E,4E)-1,5-bis(1-pentan-2-yl)-1H-imidazol-2-yl)penta-1,4-dien-3-one, showed its highest growth inhibitory activity in the TNBC cell line, MDA-MB-231, while also being effective in inhibiting the growth of ER+ cell lines to a lesser extent. Further investigations were then focused on this TNBC cell line. The mechanism of action of compound 34 was investigated by using a Human Phospho-Kinase Array, which revealed a significant decrease in p-P70S6K and p-mTOR. Additional assays confirmed the same results and also showed significant reductions in total mTOR and Total AKT as well as significant decreases in p-P70S6K and p-mTOR. Moreover, compound 34 treatment induced higher levels of p-c-JUN and p-P38, which may be indications of cell stress upon treatment. Overall our data indicate that compound 34 induces profound decreases in the activity of pro-survival pathways such as AKT/mTOR, which significantly inhibited growth of the TNBC cell line. Citation Format: Mohammad Atefi, Manee Patanapongpibul, Lynn Ma, Qiao-Hong Chen, Guangdi Wang, Yong Wu, Jay Vadgama. A 1,5-diheteroarylpenta-1,4-dien-3-one inhibits TNBC cell growth by blocking AKT/mTOR/P70S6K pathway [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B36.