Abstract 915: AKT inhibition sensitizes TNBC cells with acquired drug resistance to UM-164

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 13_Supplement; p. 915
• Main Authors: Merrill, Nathan M., Lachacz, Eric J., Gilani, Rabia A., Bao, LiWei, Wu, Zhi Fen, Merajver, Sofia D., Soellner, Matthew B.
• Format: Journal Article
• Language: English
• Published: 01.07.2018
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-915

Abstract One of the major clinical challenges in breast cancer treatment is the rapid development of resistance to targeted therapies. In light of this, there is significant interest in identifying markers of drug resistance. In particular, markers of drug resistance are sought that can be targeted to overcome acquired drug resistance. To this end, we have used reverse phase protein array (RPPA) analysis to identify differences in protein expression levels between cell lines that are sensitive or have acquired resistance to UM-164, a mechanistically novel, dual c-Src/p38 kinase inhibitor with potent anti-TNBC activity. UM-164 resistant cells acquire increased resistance also to many diverse chemotherapeutics and targeted agents relative to their drug-sensitive counterparts. We analyzed RPPA data for both UM0164-sensitive and UM-164-resistant cells and identified an increase in phospho-AKT, phospho-ERK, and phospho-FAK levels in the resistant cells. Using inhibitors of each upregulated pathway, we found that combination of UM-164 with MK2206, an inhibitor of AKT, resulted in an increased sensitization of cells to treatment with UM-164. Furthermore, formal Chou-Talalay synergy analyses demonstrate that AKT inhibitors + UM-164 are effectively synergistic in reducing the proliferation of drug-resistant cells. We further evaluated this combination treatment in mice, combining UM-164 and MK2206 in a xenograft of UM-164-resistant cells, showing significant anti-tumor efficacy. Finally, we show that the combination treatment resulted in increased cell death in ex vivo cultures of patient derived TNBC materials. Together, we have demonstrated that hyperactivation of AKT leads to UM-164 resistance and AKT inhibitors can be used to re-sensitize TNBC cells to UM-164. These results demonstrate that RPPA analyses are a valuable tool for the systematic and unbiased identification of truly actionable markers of therapeutic resistance. Citation Format: Nathan M. Merrill, Eric J. Lachacz, Rabia A. Gilani, LiWei Bao, Zhi Fen Wu, Sofia D. Merajver, Matthew B. Soellner. AKT inhibition sensitizes TNBC cells with acquired drug resistance to UM-164 [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 915.