Abstract 2392: Evaluation of synergistic PI3K/Akt and MEK5/ERK5 inhibition in triple-negative breast cancer

Abstract

Triple negative breast cancers (TNBCs) represent 15-20% of all breast cancers and are often associated with a poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Therefore, there is a need to identify survival pathways that may be targeted in TNBCs. Aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. The crosstalk between PI3K/Akt and MEK1/2/ERK1/2 has been characterized in several systems. However, new evidence suggests that MEK5/ERK5, a member of the MAPK family, is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in three TNBC cell lines: MDA-MB-231, BT549, and MDA-MB-468. We achieved Akt inhibition by using the clinically relevant inhibitors MK-2206 and Ipatasertib. We used a novel compound synthesized in our lab, SC-1-181, and the research tool, XMD8-92, to inhibit MEK5 and ERK5, respectively. Our results indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Interestingly, this signaling pattern was observed without disturbing the ERK1/2 pathway. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. Additionally, the dual inhibition strategy was determined to be synergistic in TNBCs and was nontoxic in non-neoplastic cell lines. Lastly, we evaluated the contributions of Bromodomain 4 (BDR4), an off-target effect of XMD8-92, to the synergy mechanism. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs. Citation Format: Thomas D. Wright, Christopher Raybuck, Nathan Gartland, Katy Wendekier, Darlene Monlish, Suravi Chakrabarty, Patrick T. Flaherty, Matthew E. Burow, Jane E. Cavanaugh. Evaluation of synergistic PI3K/Akt and MEK5/ERK5 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2392.