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

Abstract

The bromodomain and extra-terminal domain (BET) family inhibitors are small molecules that target the dysregulated epigenetic readers, BRD2, BRD3, BRD4 and BRDT, at various transcription-related sites, including super-enhancers. BET inhibitors are currently under investigation both in pre-clinical cell culture and tumor-bearing animal models, as well as in clinical trials. However, as is the case with other chemotherapeutic modalities, the development of resistance is likely to constrain the therapeutic benefits of this strategy. One tumor cell survival mechanism that has been studied for decades is autophagy. Although four different functions of autophagy have been identified in the literature (cytoprotective, cytotoxic, cytostatic and non-protective), primarily the cytoprotective and cytotoxic forms appear to function in different experimental models exposed to BET inhibitors (with some evidence for the cytostatic form). This review provides an overview of the cytoprotective, cytotoxic and cytostatic functions of autophagy in response to BET inhibitors in various tumor models. Our aim is to determine whether autophagy targeting or modulation could represent an effective therapeutic strategy to enhance the response to these modalities and also potentially overcome resistance to BET inhibition.

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

“…The efficacy of BET inhibitors as an approach to target senescence has been investigated in a number of studies, including those from our laboratories with senolytic as well as senomorphic activity being demonstrated ( 85 , 130 , 192 ). The relationship between the BET family and autophagy has recently has been reviewed by our laboratory ( 198 ).…”

The Cytoprotective Role of Autophagy in Response to BRAF-Targeted Therapies

“…Autophagy involves the recycling of cytoplasmic components, such as the mitochondria and endoplasmic reticulum, and/or damaged organelles, for the maintenance of cellular homeostasis by the generation of energy and metabolic intermediates [3,8]. Autophagy and autophagic flux (i.e., autophagy proceeding to completion) are induced in response to various stimuli such as starvation, hypoxia, oxidative stress, endoplasmic reticulum (ER) stress and protein aggregation [3,9].…”

“…In addition to the epigenetic readers/regulators which may control the fate of the autophagic flux, as discussed in previous publications [8,34], several studies investigated the potential control of the autophagic machinery by microRNAs (miRNAs). miRNAs are non-coding RNAs that bind the 3 -untranslated region (3 -UTR) of target mRNAs, inhibiting their translation or causing their degradation, which ultimately results in the suppression of gene expression [35].…”

“…This manuscript is one of a series of papers [1][2][3][4][5][6][7][8] from our research group evaluating the potential contribution(s) of the autophagic machinery to the action of various antineoplastic modalities. The overarching goal of these efforts has been to determine whether there are particular therapeutic interventions where the preclinical data, and, where available, clinical trials, support the inclusion of autophagy inhibitors as an adjuvant approach to improve therapeutic outcomes.…”

Making the Case for Autophagy Inhibition as a Therapeutic Strategy in Combination with Androgen-Targeted Therapies in Prostate Cancer

“…This manuscript is one of a series of papers that were designed to evaluate the role(s) of autophagy in response to various cancer therapeutic modalities. Our previous publications assessed the influence of autophagy in tumor cells on the response/sensitivity to radiation [1], cisplatin [2], microtubule poisons [3], hormonal therapies in estrogen positive breast cancer [4], PARP inhibitors [5], topoisomerase I poisons [6], temozolomide [7], BET family inhibitors [8] and, most recently, BRAF-targeted therapies [9]. This series of papers will ultimately delineate whether there are particular therapeutic modalities where the preclinical data, and where available, clinical trials, support the inclusion of autophagy inhibition or modulation as an adjuvant approach.…”