Abstract 2365: Dual inhibition of the PI3k/Akt and MEK5/ERK5 pathways in tamoxifen resistant breast cancer

Abstract

Abstract Approximately 70% of breast cancers are considered estrogen receptor alpha (ER) and/or progesterone receptor (PR) positive, and their growth is primarily driven by the hormone estrogen. Initially these cancers are responsive to endocrine therapies such as tamoxifen. However, over time patients become resistant to conventional endocrine therapy and treatment becomes more difficult. Tamoxifen resistance occurs due to several mechanisms: loss of ER expression, gain of function mutations, pharmacological tolerance, alterations of co-activators, and ligand independent activation of ER by various kinase cascades. 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 therapy resistant cancers. MEK5/ERK5 has been shown to promote ER alpha driven transcription in ER+ breast cancers and actin reorganization and metastasis in ER- breast cancers. Furthermore, MEK5/ERK5 promotes hormone independent tumorigenesis in breast cancer. Our lab has previously investigated these pathways in hormone independent breast cancers, TNBC (triple negative breast cancer). Our previous results indicate that combinations of PI3k/Akt and MEK5/ERK5 blockade are promising because they inhibit both the pro-proliferative and pro-metastatic pathways in TNBC. Additionally, PI3k/Akt and MEK5/ERK5 inhibition was shown synergistically reduce viability in a diverse panel of cell lines (TNBC, ER+, and Triple Positive). Based on these initial results we hypothesize that PI3k/Akt and MEK5/ERK5 inhibition decreases viability via a hormone independent mechanism: perhaps by reducing the cytosolic sequestration of Bad. In this study we investigate the utility PI3k/Akt and MEK5/ERK5 inhibition in a MCF-7 TamR cell line. The goal of our study is to elucidate the roles of PI3k/Akt/mTOR and MEK5/ERK5 in endocrine resistant breast cancer and broaden the scope of a dual inhibition strategy. Citation Format: Thomas D. Wright, Mahmud Hasan, Paula Witt-Enderby, Jane Cavanaugh. Dual inhibition of the PI3k/Akt and MEK5/ERK5 pathways in tamoxifen resistant 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 2365. doi:10.1158/1538-7445.AM2017-2365