Abstract P3-05-04: AKT antagonist AZD5363 targets estrogen receptor (ER) function in endocrine resistant breast cancer (BC) and synergises with fulvestrant in vivo

AIM: To evaluate the efficacy and functional consquences of combining AZD5363 with endocrine therapy in pre-clinical models of endocrine-sensitive and resistant ER+ BC. BACKGROUND: The PI3K/AKT/mTOR signalling pathway plays an important role in BC. Its close interaction with ER signalling becomes more complex and inter-dependent with acquisition of endocrine resistance. Targeting the mTOR pathway in combination with endocrine therapy has shown clinical utility. However, a negative feedback loop exists downstream of the PI3K/AKT/mTOR pathway with mTOR inhibition leading to increased activation of IGFR1-dependent AKT activity potentially negating long-term benefit. Direct blockade of AKT in combination with endocrine therapy, may provide a better rationale for treatment of endocrine-resistant BC, impacting on both cell survival/apoptosis and ER ligand-independent signaling. In this investigation, we assessed the efficacy of AZD5363, a pan-AKT inhibitor with endocrine therapies in pre-clinical models of endocrine sensitive and resistant ER+ BC and its impact on molecular and cellular response. METHODS: Inhibition of AKT using AZD5363 was examined in 5 ER+ BC lines before and after adaptation to long-term estrogen deprivation (LTED) or tamoxifen (TAMR). The effects of AZD5363 on cell proliferation were determined alone and in combination with endocrine treatment and feedback upregulation and activation of receptor tyrosine kinases (RTKs) was examined by western blotting. ER-transactivation was measured with an estrogen-response element (ERE)-linked luciferase reporter construct and confirmed using chromatin-immunoprecipitation. Global gene expression analysis was used to identify pathways associated with response. Xenografts were treated with AZD5363 ± fulvestrant to determine in vivo effects. RESULTS: AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50 CONCLUSION: These data suggest that AZD5363 plus fulvestrant may be effective in BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response. These data strongly support the need for clinical evaluation. Citation Format: Lesley-Ann Martin, Stephanie K Guest, Sunil Pancholi, Ricardo Ribas, Qiong Gao, Nikiana Simigdala, Aradhana Rani, Barry Davies, Stephen Johnston, Mitch Dowsett. AKT antagonist AZD5363 targets estrogen receptor (ER) function in endocrine resistant breast cancer (BC) and synergises with fulvestrant in vivo [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-04.