Abstract 5478: Combination of fulvestrant with the allosteric Akt inhibitor MK-2206 promotes anti-tumor activity in estrogen deprivation-resistant estrogen receptor positive breast cancer

Abstract

Abstract Introduction: Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway through gene mutation, most frequently in PIK3CA, is common in estrogen receptor-positive (ER+) breast cancer (BC) and deregulation of PI3K signaling contributes to endocrine resistance. These data suggest that proteins within the PI3K/Akt cascade are important therapeutic targets for patients who experience relapse despite adjuvant endocrine treatment. We have demonstrated previously that simultaneous inhibition of PI3K catalytic subunits and ER (through estrogen deprivation) activates cell death in estrogen-dependent ER+ BC cells (Cancer Res 69:3955, 2009). In order to develop rationales for combination therapies in the advanced disease setting we tested a clinical grade Akt inhibitor, MK-2206 in both estrogen-dependent BC cells and in BC cells that had lost the requirement for estrogen due to long-term estrogen deprivation (LTED). Methods: The effects of MK-2206 on cell signaling and apoptosis were determined in a panel of growth-arrested ER+ BC cells following short-term estrogen deprivation (STED) and in estrogen-independent MCF7 and T47D cells established following LTED. The impact of estrogen deprivation and treatment with the ER down-regulator fulvestrant on MK-2206 treatment-induced apoptosis was assessed in STED and LTED cells. We also determined the activity of MK-2206 with and without fulvestrant in vivo in MCF7 LTED xenografts, a model for aromatase inhibitor-resistant ER+ breast cancer. Results: MK-2206-induced apoptosis was most marked in STED cells with PIK3CA mutation and PTEN loss, indicating that ER+ BC with PI3K pathway mutations will be most sensitive to MK-2206 treatment. Estradiol antagonized MK2206-induced apoptosis following STED, emphasizing a role for estrogen-deprivation therapy in promoting Akt inhibitor activity. MCF7 LTED cells exhibited increased ER expression and resistance to MK-2206 which was reversed by treatment with fulvestrant. In contrast, T47D LTED cells exhibited ER loss and resistance to MK-2206 that was not overcome by fulvestrant. In MCF7 LTED xenografts the combination MK-2206 with fulvestrant showed a synergistic effect on inhibiting tumor cell proliferation and tumor growth. Conclusions: In estrogen-dependent ER+ BC cells with PIK3CA mutation or PTEN loss, acute estrogen deprivation increases the apoptotic effects of MK-2206 providing a rationale for Akt/aromatase inhibitor combinations in the first line setting. In ER+ BC cells that have lost the requirement for estrogen following LTED, fulvestrant antagonizes ER function and promotes Akt inhibitor activity suggesting that this combination would be appropriate for testing as a second line approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5478. doi:10.1158/1538-7445.AM2011-5478