Abstract P1-13-02: Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer

Abstract

Abstract While anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer, relapse after remission continues to be a serious limitation to the effectiveness of these therapies. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into a state of autophagy/senescence from which a subpopulation ultimately escapes, potentially contributing to disease recurrence. ER+ MCF-7 breast tumor cells that were induced into autophagy/senescence by Fulvestrant + Palbociclib in vitro were exposed to the autophagy inhibitors, chloroquine and bafilomycin, prior to as well as after growth arrest. However, autophagy inhibition only moderately enhanced the response to therapy and, at best, delayed proliferative recovery. These findings were confirmed by genetic inhibition of autophagy. Despite clear entry into a state of senescence, the Bcl-xl inhibitor and senolytic ABT-263 (navitoclax) failed to promote tumor cell death; this is likely a consequence of high levels of survivin in the MCF-7 breast tumor cell line. However, the BET inhibitor, ARV-825, eliminated a large fraction of the senescent cell population and significantly delayed proliferative recovery. Cell death did not appear to be a consequence of increased apoptosis. Additionally, analysis of three database sets demonstrated that higher breast cancer expression of BRD4, a primary target of ARV-825, correlated with lower recurrence-free survival compared to patients with cancers expressing lower levels of BRD4. These studies indicate that administration of BET inhibitors, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients by prolonging progression-free survival. Citation Format: Ryan Michael Finnegan. Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-02.