Dual inhibition of the MEK5 and PI3K pathways synergistically reduces proliferation and viability in triple negative breast cancer cells


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Thomas Wright1,Jane Cavanaugh1,Christopher Raybuck2,Katy Wendekier2
1Duquesne Univeristy,2Duquesne University

Abstract

Background

Aberrations in the MAPK/extracellular signal-regulated kinase (MEK/ERK) and phosphoinositide-3-kinase (PI3K) pathways have been linked to increased proliferation and survival in triple negative breast cancer (TNBC) cells. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. Promising combinations of MEK and PI3K inhibition have been evaluated in phase I clinical trials for various cancer types. However, these clinical trials have had limited efficacy and have yet to encompass the MEK5/ERK5 pathway, which has been shown to promote cell survival. 

Method

The goal of this study was to examine the crosstalk between the MEK1/2, MEK5, and PI3K pathways and determine the most promising combination of the MEK1/2, ERK5, and PI3K inhibitors, U0126, XMD8-92, and LY294002, respectively, in a diverse panel of triple negative breast cancer cell lines: BT549, MDA-MB-231, and MDA-MB-468. 

Results

Our results indicate that dual inhibition of the MEK5 and PI3K pathways synergistically reduced proliferation (45.53%) in MDA-MB-231 TNBC cells. In contrast, inhibition of ERK1/2 alone or in combination with PI3K or ERK5 inhibition yielded mixed responses. Interestingly, dual inhibition of the MEK5 and PI3K pathways increased the activity of the MEK1/2 pathway.

Conclusion

These data suggest that crosstalk between these kinases occurs and dual inhibition of PI3K and ERK5 may be a novel therapeutic approach for treating TNBC.