ABSTRACT
While endocrine therapy remains the mainstay of treatment for ER-positive, HER2-negative breast cancer, tumor progression and disease recurrence limit the utility of current standards of care. While existing therapies may allow for a prolonged progression-free survival, however, the growth-arrested (essentially dormant) state of residual tumor cells is not permanent and is frequently a precursor to disease relapse. Tumor cells that escape dormancy and regain proliferative capacity also tend to acquire resistance to further therapies. The cellular process of autophagy has been implicated in the adaptation, survival, and reactivation of dormant cells. Autophagy is a cellular stress mechanism induced to maintain cellular homeostasis. Tumor cells often undergo therapy-induced autophagy which, in most contexts, is cytoprotective in function; however, depending on how the autophagy is regulated, it can also be non-protective, cytostatic, or cytotoxic. In this review, we explore the literature on the relationship(s) between endocrine therapies and autophagy. Moreover, we address the different functional roles of autophagy in response to these treatments, exploring the possibility of targeting autophagy as an adjuvant therapeutic modality together with endocrine therapies.
ABSTRACT
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. 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 states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival.
