Antiestrogens (AEs) have long been a standard treatment for estrogen receptor-positive (ER+) breast cancer patients. However, antiestrogen resistance, either de novo or acquired, is a major hurdle for effective therapy in breast cancer patients. To address this, the underlying mechanisms of antiestrogen resistance must be understood. One common mechanism by which AE resistant cells thrive is by overexpressing BCL2 and its antiapoptotic family members, which allows cancer cells to survive under conditions that would normally cause apoptosis. We discovered that the BH3-mimetic, obatoclax (GX15-070), significantly reduces cell proliferation and, in combination with fulvestrant or tamoxifen, results in a synergistic inhibition of cell growth in AE resistant breast cancer cells. Obatoclax exhibits potency against BCL2, BCL-XL, BCLW, MCL1, and A1 and is currently being used in clinical trials directed at lymhomas and leukemia. However, the molecular mechanisms of cell death by obatoclax are unclear. We show that obatoclax induces apoptosis and autophagosome formation in AE-resistant breast cancer cells. To compensate for the increase in autophagosomal formation as measured by LC3, obatoclax also induces lysosome formation to prepare for cellular breakdown. This study is the first to show that obatoclax inhibits prosurvival autophagy by preventing the degradation of LC3 and p62 through a cathepsin-dependent mechanism. Furthermore, overexpression of BCL2 in breast cancer cells “primes” the cells with BH3-only proteins and renders the cancer cell sensitive to treatment with obatoclax. Collectively, these data support exploration of clinical trials combining an AE and the BCL2 inhibitor, obatoclax, for the treatment of AE-resistant breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2783. doi:1538-7445.AM2012-2783

©2012 American Association for Cancer Research
2012