The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

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.

Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors

“…These results are, in part, consistent with data from our laboratory, where we investigated the potential utilization of ARV-825 as a senolytic in ER+ breast cancer models [38]. Initially, senescence was induced in both MCF-7 and T47D cells using a combination of fulvestrant plus palbociclib (F+P), as confirmed by beta-galactosidase staining and the quantification of senescence using C 12 FDG, a beta-galactosidase florescent metabolite, as well as by monitoring SASP markers.…”

“…Consistent with the differential sensitivity observed, the SKOV-3 and HEY cells demonstrated a higher apoptosis response as compared to the A2780 and HO-8910 cell lines, in a dose-dependent manner. BRD4 and c-Myc levels were downregulated in the four cell lines upon JQ1 treatment, as would have been expected considering that these are established downstream targets of JQ1 and other BET inhibitors [38,48].…”

“…Furthermore, additional autophagic markers and assays, and particularly genetic strategies, will be required to rigorously establish the role of autophagy induced in each tumor model, as emphasized in the guidelines established by Klionsky et al [95]. Cytotoxic in senescent population [38]…”

Advances in research on autophagy mechanisms in resistance to endometrial cancer treatment

“…Finnegan et al. found that inhibiting autophagy with chloroquine and bafilomycin A1 and silencing the autophagy-regulating gene ATG5 did not sensitize Fulvestrant + Palbociclib to breast tumor cells, indicating that in breast tumors, the autophagy mechanism is non-protective under the action of Fulvestrant + Palbociclib ( 41 ). In summary, different anti-tumor drugs play their respective important roles by altering autophagy mechanisms under different conditions.…”

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

“…The most frequently utilized CDKi, usually in combination with either fulvestrant or letrazole, is palbociclib ( 130 , 169 ). Palbociclib is a potent inducer of the senescence phenotype; for example, Jost et al.…”