MM-141, a bispecific antibody inhibitor of PI3K/AKT/mTOR, attenuates tumor growth and potentiates everolimus in mouse models of anti-hormonal therapy-resistant ER/PR plus breast cancer.

Purpose: PI3K/AKT/mTOR network adaptation through the upregulation of receptor tyrosine kinases signaling and subsequent re-activation of AKT is a common resistance mechanism to chemotherapies and small molecule inhibitors of mammalian target of rapamycin (mTOR). In order to block this feedback loop, MM-141, a tetravalent bispecific antibody directed at IGF-1R and ErbB3, was co-administered in combination with everolimus in various preclinical models of cancer. As everolimus is an approved therapy for women with advanced hormone receptor-positive breast cancer after failure of treatment with aromatase inhibitor, we have specifically focused on the analysis of a MM-141/everolimus combination in a hormone refractory breast cancer mouse model. Experimental Procedures: Estrogen-supplemented mice bearing BT-474-M3 ER+/PR+ breast cancer xenografts were implanted with tamoxifen-releasing pellets. Following the development of resistance to tamoxifen, these mice were randomized into pharmacodynamics and efficacy assessment sub-groups, and treated with everolimus, MM-141 or the combination. In pharmacodynamics assessment subgroups, the tumors were harvested 24 hours following the last MM-141 dose and profiled for a panel of molecular markers of activation of PI3K/AKT/mTOR pathway. In addition we have assessed the activity of MM-141, everolimus or the combination in cell culture on a broad panel of breast cancer cell lines using CellTiter-Glo® Luminescent Cell Viability Assay. Data Summary: We have demonstrated that MM-141 has significant anti-tumor activity in the ER+/PR+ BT-474-M3 breast cancer xenograft model and strongly potentiates the activity of everolimus in a tamoxifen-resistant setting. Pharmacodynamic profiling illustrates that the combination treatment achieves sustained inhibition of PI3K/AKT/mTOR signaling. MM-141 mediates the resistance to everolimus by inhibiting IGF-1R, ErbB3, and IRS-1 and controlling the re-activation of AKT. Further, MM-141 is able to inhibit the proliferation of a panel of breast cancer cell lines in vitro. This inhibition is increased upon co-treatment of the cells with MM-141 and everolimus. Conclusions: Our in vivo preclinical studies show that MM-141 combines synergistically with the mTOR inhibitor everolimus and this combination is active in reversing acquired resistance to the anti-hormonal therapy tamoxifen. This potentiation of everolimus by MM-141 is tied to its ability to reverse the re-activation of AKT signaling induced by this mTOR blocker. We demonstrate that this potentiation phenomenon is common in a wide panel of breast cancer cell lines. Overall, our results suggest that MM-141 could be a potentially valuable addition to the breast cancer treatment regimens comprising an mTOR inhibitor and an anti-hormonal therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C169. Citation Format: Sharlene Adams, Jason Baum, Breanne Sparta, Victoria Rimkunas, Jian Tang, Emily Pace, Shoshana Rosenthal, Adam Camblin, Sergio Iadevaia, Akos Czibere, Ulrik Nielsen, Alexey Lugovskoy. MM-141, a bispecific antibody inhibitor of PI3K/AKT/mTOR, attenuates tumor growth and potentiates everolimus in mouse models of anti-hormonal therapy-resistant ER/PR+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C169.