Abstract 4117: Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast cancer

Abstract

Abstract Triple negative breast cancers (TNBCs) are especially lethal due to their high metastatic potential and propensity to recur. TNBCs comprise the only subset of breast cancer for which there are no FDA-approved targeted therapies. We have developed a mechanistically novel dual c-Src/p38 inhibitor, UM-164, that has potent in vivo anti-TNBC activity. However, single-agent targeted therapies are prone to resistance and rational drug combinations can overcome or prevent resistance. We developed TNBC cells lines that are resistant to UM-164. Significant morphology and cell signaling changes occurred in the drug-resistant cell lines. Most crucial is the observation that in drug-resistant cell lines the activation of c-Src and/or p38 does not return in the presence of UM-164, suggesting that resistance is not occurring via constitutive activation enabling mutations of c-Src and/or p38 kinases. However, compared to their drug-sensitive counterparts, the UM-164-resistant cells have significantly hyperactivated MEK1/2 and ERK1/2 signaling when treated with UM-164. Thus, we tested combinations of UM-164 + MEK1/2 inhibitors in several TNBC cell lines and patient derived xenografts. We found that trametinib (Mekinist®, an FDA-approved inhibitor of MEK1/2) is synergistic (Chou-Talalay CI at ED90 = 0.4, CI < 1 denotes synergy) with UM-164 to inhibit the growth of UM-164-resistant MDA-MB-231 and SUM-149 cell lines. These results support our hypothesis that activation of MEK/ERK signaling can act as an escape mechanism that leads to resistance to UM-164. Future research into rational combinations of targeted therapies delivered in data driven schedules may hold the key to improving survival in TNBC. Citation Format: Rabia A. Gilani, Eric J. Lachacz, Sameer Phadke, Li Wei Bao, Xu Cheng, Evelyn M. Jiagge, Matthew B. Soellner, Sofia D. Merajver. Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4117. doi:10.1158/1538-7445.AM2017-4117