Abstract 6233: APG-2575, a clinical stage BCL-2 selective inhibitor, sensitizes estrogen receptor-positive breast cancers to standard therapies in the preclinical models

Abstract

Abstract Breast cancer is a heterogeneous disease with at least four categories according to the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. In ER+ breast cancer, anti-estrogen therapies with tamoxifen, or CDK4/6 plus aromatase inhibitors remain the standard endocrine therapy, whereas the combination of CDK4/6-targeted therapy plus fulvestrant (an ER degrader) follows when the disease progresses on the hormonal therapy. However, drug resistance to the current therapies frequently emerges and patients relapse after the initial remission. Developing more effective treatments becomes an urgent need. Among four subsets of breast cancer, ER+ breast cancer exhibits the highest BCL-2 expression (83% compared with 50% for HER2+, 18.5% for basal-like, and 41.4% for marker-null subtypes). Thus, inhibition of BCL-2 which triggers apoptosis of cancer cells may become an effective therapy and synergizes the current therapies. APG-2575 is a BCL-2 selective inhibitor currently in clinical trials in patients with hematologic malignancies. Here, in preclinical xenograft models of ER+ breast cancer in mice, we evaluated whether APG-2575 enhanced the sensitivity to tamoxifen or CDK4/6-targeted (i.e., palbociclib or palbociclib plus fulvestrant) therapy. The results revealed that, in ER+ MCF-7-derived xenografts, double or triple combination treatment with APG-2575 plus tamoxifen, palbociclib, or palbociclib and fulvestrant significantly attenuated tumor progression in comparison with single or double agents treatments without APG-2575. The combination of APG-2575 plus tamoxifen achieved 4/6 partial tumor regression (PR; 67%) and 2/6 complete regression (CR; 33%) in xenograft-bearing mice. The combination with palbociclib resulted in 4/6 stable disease (SD; 67%) and 1/4 CR (25%). The triple combination with palbociclib plus fulvestrant caused 3/4 PR (75%). The combination benefits were further investigated in tamoxifen-resistant models. The triple combination with palbociclib plus fulvestrant demonstrated superior antitumor activity in tamoxifen-resistant ER+ MCF-7 xenografts. In a patient-derived, tamoxifen-resistant, ER+ breast cancer xenograft model, APG-2575 plus palbociclib achieved 100% overall response rate (1/3 CR, 2/3 PR). The results suggest that BCL-2 inhibition substantially improves the current therapies in ER+ breast cancer in the preclinical setting. The mechanisms underlying the synergistic effect of the combinations are currently under investigation and will be included in our presentation. Taken together, we demonstrated that combining APG-2575 with tamoxifen or palbociclib therapies substantially enhances antitumor activity and overcomes tamoxifen resistance in the preclinical models of ER+ breast cancer, suggesting a novel strategy for the clinical development of BCL-2 inhibitors in ER+ breast cancers. Citation Format: Douglas D. Fang, Qiuqiong Tang, Ran Tao, Guoqin Zhai, Qixin Wang, Dajun Yang, Yifan Zhai. APG-2575, a clinical stage BCL-2 selective inhibitor, sensitizes estrogen receptor-positive breast cancers to standard therapies in the preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6233.