BET proteins regulate homologous recombination‐mediated DNA repair: BRCAness and implications for cancer therapy

Abstract

Bromodomain and Extra-Terminal (BET) proteins are historically involved in regulating gene expression and BRD4 was recently found to be involved in DNA damage regulation. Aims of our study were to assess BRD4 regulation in homologous recombination-mediated DNA repair and to explore novel clinical strategies through the combinations of the pharmacological induction of epigenetic BRCAness in BRCA1 wild-type triple negative breast cancer (TNBC) cells by means of BET inhibitors and compounds already available in clinic.Performing a dual approach (chromatin immunoprecipitation and RNA interference), the direct relationship between BRD4 and BRCA1/RAD51 expression was confirmed in TNBC cells. Moreover, BRD4 pharmacological inhibition using two BET inhibitors (JQ1 and GSK525762A) induced a dose-dependent reduction in BRCA1 and RAD51 levels and is able to hinder homologous recombination-mediated DNA damage repair, generating a BRCAness phenotype in TNBC cells. Furthermore, BET inhibition impaired the ability of TNBC cells to overcome the increase in DNA damage after platinum salts (i.e., CDDP) exposure, leading to massive cell death, and triggered synthetic lethality when combined with PARP inhibitors (i.e., AZD2281). Altogether, the present study confirms that BET proteins directly regulate the homologous recombination pathway and their inhibition induced a BRCAness phenotype in BRCA1 wild-type TNBC cells. Noteworthy, being this strategy based on drugs already available for human use, it is rapidly transferable and could potentially enable clinicians to exploit platinum salts and PARP inhibitorsbased treatments in a wider population of TNBC patients and not just in a specific subgroup, after validating clinical trials.

APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

“…Targeting cell cycle is a new emerging strategy that was particularly effective in luminal-like breast cancer in reverting endocrine resistance [93], but interesting data suggest a possible role of CDK4-6 inhibitors also as chemo-companions, since CDK6 may interfere with Pt-induced cell death through FOXO3 [94]. The present study, therefore, supports the rationale of finding optimal DNA-repair -focused companions, capable to both synergize with chemotherapy and to revert potential resistance mechanisms that could defeat the DNA -damaging potential of Pt-salts [12]. Synthetic lethality involving the inhibition of the APE1 endonuclease activity is only recently emerging in literature [95,96].…”

“…As the anthracyclinebased regimen seems to bridge the gap between the NPM1 low and high groups, these data suggest that there is a subgroup of TNBC patients that not only is potentially prone to respond, but that could be burdened by a worse outcome if different therapeutic strategies were put in place. These results are of particular clinical interest since DNA-damaging strategies are an emerging opportunity for the treatment of TNBC, but a solid predictive marker is currently needed [12,17,92]. The inability to translate this difference on OS could be due to the small sample size, post-relapse treatments or underlying differences in terms of tumor biology.…”

“…Among BC subtypes, triple negative breast cancer (TNBC) represents a challenge because of its heterogeneity and the absence of a well-defined druggable target, restricting clinical decision making to chemotherapy [8][9][10]. Different approaches have been explored to better dissect the TNBC profile in order to optimize therapeutic choices and exploit new strategies, such as genotoxic agents and interference with different DNA repair pathways [11,12]. Among the therapeutic options already employed in the clinical practice of several tumors including TNBC, platinum (Pt)-based compounds emerge for their ability to interfere with several cellular processes, including DNA replication and transcription [13][14][15].…”

Nanoparticles Loaded with the BET Inhibitor JQ1 Block the Growth of Triple Negative Breast Cancer Cells In Vitro and In Vivo

“…Many approaches are currently under investigation, including the search for molecular targets, potential candidates for selective treatments [20]. For this purpose, targeting histone activity in regulating gene expression by acting on epigenome "readers" is a promising approach for the treatment of various malignancies, including TNBC [9,21,22]. In particular, JQ1 is a first-in-class selective BET bromodomain inhibitor [23], which acts by competitively binding with high affinity to the acetyl-lysine hydrophobic pocket of BRD4 [24,25].…”

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

“…In addition to directly target these repair proteins, combining a PI3K pathway inhibitor and a PARP inhibitor has shown synergistic anti-tumor effects in SCLC and warrants further consideration for clinical trials [97]. Targeting epigenetic factors such as BET family members cause defects in DSB repair and might provide beneficial effects in combination with PARP inhibitors [98]. Preclinical studies using BET inhibitor and PARP inhibitor combination have shown the superior anti-tumor efficacy compared to either agent alone in various cancer types [99][100][101].…”