An updated patent review of BRD4 degraders.

INTRODUCTION: Bromodomain-containing protein 4 (BRD4), an important epigenetic reader, is closely associated with the pathogenesis and development of many diseases, including various cancers, inflammation, and infectious diseases. Targeting BRD4 inhibition or protein elimination with small molecules represents a promising therapeutic strategy, particularly for cancer therapy. AREAS COVERED: The recent advances of patented BRD4 degraders were summarized. The challenges, opportunities, and future directions for developing novel potent and selective BRD4 degraders are also discussed. The patents of BRD4 degraders were searched with SciFinder and Cortellis Drug Discovery Intelligence database. EXPERT OPINION: BRD4 degraders exhibit superior efficacy and selectivity to BRD4 inhibitors, given their unique mechanism of protein degradation instead of protein inhibition. Excitingly, RNK05047 is now in phase I/II clinical trials, indicating that selective BRD4 protein degradation may offer a viable therapeutic strategy, particularly for cancer. Targeting BRD4 with small molecule BRD4 degraders provides a promising approach with the potential to overcome therapeutic resistance for treating various BRD4-associated diseases.

BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer.

The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.

Clinical analysis and treatment progress of NUT carcinoma in the nasal cavity and sinuses: a retrospective study from a single institution.

OBJECTIVE: Nuclear protein in testis (NUT) carcinoma is characterized by NUT gene rearrangement on chromosome 15. The objective of this study was to investigate the clinical features, immunohistochemistry, treatment, diagnosis and prognosis of sinonasal NUT carcinoma specifically. METHODS: Clinical data for 10 cases of NUT cancer confirmed by pathology were retrospectively analyzed, and the relevant literature was reviewed. RESULTS: Among the 10 patients, 6 were males, and 4 were females. The median age was 34 years (15-69 years). Nine patients presented with locally advanced cT4a stage. The most common treatment was complete resection combined with radiotherapy, chemotherapy, and targeted therapy. All 10 patients had pathologically poorly differentiated or undifferentiated carcinoma. Furthermore, immunohistochemical staining showed that NUT protein was positive in all 10 patients, and most cases expressed p63, p40 and CK. The Ki-67 positive index of 8 patients ranged from 40 to 80%, with a median of 50%, and NUTM1 gene disruption was detected in both of the remaining cases by FISH. As of April, 2023, all patients were followed up with for 1-51 months, with a median follow-up time of 14 months. Three patients died due to widespread systemic metastasis, 3 relapsed, and 4 had no recurrence or metastasis. CONCLUSION: Sinonasal NCs (NUT carcinomas) is a rare and highly aggressive malignant tumor with rapid progression and a poor prognosis. Correct histopathological diagnosis is the primary prerequisite for determining appropriate treatment. There are currently no effective treatment options for NCs. Targeted therapy may become an effective method to treat NCs.

Inhibitor of bromodomain and extraterminal domain proteins decreases transcription of Cd33 in the brain of mice subjected to systemic inflammation; a promising strategy for neuroprotection.

The neuroinflammation is a crucial component of virtually all neurodegenerative disorders, including Alzheimer's disease (AD). The bacterial lipopolysaccharide (LPS), a potent activator of the innate immune system, was suggested to influence or even trigger the neuropathological alterations in AD. LPS-induced neuroinflammation involves changes in transcription of several genes, thus controlling these molecular processes may be a potentially efficient strategy to attenuate the progression of AD. Since genome-wide association studies showed that the majority of AD-related genetic risk factors (AD-GRF) are connected to the immune system, our aim was to identify AD-GRF affected in the hippocampus by LPS-induced systemic inflammatory response (SIR). Moreover, we analysed the role of bromodomain and extraterminal domain (BET) proteins, the readers of the acetylation code, in controlling the transcription of selected AD-GRF in the brain during neuroinflammation. In our study, we used a mouse model of LPS-induced SIR and mouse microglial BV2 cells. JQ1 was used as an inhibitor of BET proteins. The level of mRNA was analysed using microarrays and qPCR. Our data demonstrated that among the established AD-GRF, only the expression of Cd33 was significantly upregulated in the hippocampus during SIR. In parallel, we observed an increase in the expression of Brd4, a BET family member. JQ1 prevented an LPS-evoked increase in Cd33 expression in the hippocampus of mice. Moreover, JQ1 reduced Cd33 expression in BV2 microglial cells stimulated with blood serum from LPS-treated mice. Our study suggests that LPS-evoked SIR may increase Cd33 gene expression in the brain, and inhibition of BET proteins through suppression of Cd33 expression could be a promising strategy in prevention or in slowing down the progression of neuroinflammation and may potentially affect the pathomechanism of AD.

Arsenic-induced downregulation of BRWD3 suppresses proliferation and induces apoptosis in lung adenocarcinoma cells through the p53 and p65 pathways.

Bromodomain and WD-repeat domain-containing protein 3 (BRWD3) exhibits high expression in lung adenocarcinoma (LUAD) tissues and cells; however, its function in arsenic-induced toxicological responses remains unclear. This study aimed to investigate BRWD3 expression in response to arsenic-induced conditions and its impact on the proliferation and apoptosis of LUAD cell line SPC-A1 upon BRWD3 knockdown. The results revealed a decrease in BRWD3 expression in SPC-A1 cells treated with sodium arsenite (NaAsO2), but not sodium arsenite's metabolites. BRWD3 knockdown suppressed cell proliferation and induced apoptosis in SPC-A1 cells. Western blot analysis revealed that BRWD3 knockdown resulted in the upregulation of p53, phospho-p53-Ser392, and its downstream factors including MDM2, Bak, and Bax. Additionally, we observed the downregulation of p65, phospho-p65-Ser276, phospho-p65-Ser536, and its downstream factors, including IκBα, BIRC3, XIAP and CIAP1. Moreover, polymerase chain reaction analysis showed that BRWD3 knockdown also resulted in the downregulation of proliferation-related genes and upregulation of apoptosis-related genes. In conclusion, BRWD3 mediated proliferation and apoptosis via the p53 and p65 pathways in response to arsenic exposure, suggesting potential implications for LUAD treatment through BRWD3 downregulation by arsenic.

Synthesis, SAR, and application of JQ1 analogs as PROTACs for cancer therapy.

JQ1 is a wonder therapeutic molecule that selectively inhibits the BRD4 signaling pathway and is thus widely used in the anticancer drug discovery program. Due to its unique selective BRD4 binding property, its applications are further extended in the design and synthesis of bi-functional PROTAC molecules. This BRD4 targeting PROTAC molecule selectively degrades the protein by proteolysis. There are several modifications of JQ1 known to date and extensively explored for their applications in PROTAC technology by several research groups in academia as well as industry for targeting oncogenic genes. In this review, we have covered the discovery and synthesis of the JQ1 molecule. The SAR of the JQ1 analogs will help researchers develop potent JQ1 compounds with improved inhibitory properties against malignant cells. Furthermore, we explored the potential application of JQ1 analogs in PROTAC technology. The brief history of the bromodomain family of proteins, as well as the obstacles connected with PROTAC technology, can help comprehend the context of the current research, which has the potential to improve the drug development process. Overall, this review comprehensively appraises JQ1 molecules and their prior implementation in PROTAC technology and cancer therapy.

In Silico Design, Chemical Synthesis, Biophysical and In Vitro Evaluation for the Identification of 1-ethyl-1H-pyrazolo[3,4-b]pyridine-based BRD9 Binders.

In this work, we report the identification of novel bromodomain-containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure-based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1-ethyl-1H-pyrazolo[3,4-b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C-4 and C-6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (2-20) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (5, 11, 12, and 19) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low-micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target.

SARS-CoV-2 E protein interacts with BRD2 and BRD4 SEED domains and alters transcription in a different way than BET inhibition.

Bromodomain and extra-terminal (BET) proteins are relevant chromatin adaptors involved in the transcriptional control of thousands of genes. Two tandem N-terminal bromodomains are essential for chromatin attachment through acetyl-histone recognition. Recently, the BET proteins members BRD2 and BRD4 were found to interact with the SARS-CoV-2 envelope (E) protein, raising the question of whether the interaction constitutes a virus hijacking mechanism for transcription alteration in the host cell. To shed light on this question, we have compared the transcriptome of cells overexpressing E with that of cells treated with the BET inhibitor JQ1. Notably, E overexpression leads to a strong upregulation of natural immunity- and interferon response-related genes. However, BET inhibition results in the downregulation of most of these genes, indicating that these two conditions, far from causing a significant overlap of the altered transcriptomes, course with quite different outputs. Concerning the interaction of E protein with BET members, and differing from previous reports indicating that it occurs through BET bromodomains, we find that it relies on SEED and SEED-like domains, BET regions rich in Ser, Asp, and Glu residues. By taking advantage of this specific interaction, we have been able to direct selective degradation of E protein through a PROTAC system involving a dTAG-SEED fusion, highlighting the possible therapeutic use of this peptide for targeted degradation of a viral essential protein.

A novel PROTAC molecule dBET1 alleviates pathogenesis of experimental autoimmune encephalomyelitis in mice by degrading BRD4.

Neuroinflammation and neurodegeneration are hallmarks of multiple sclerosis (MS). Bromodomain-containing protein 4 (BRD4), a bromodomain and extra-terminal domain (BET) protein family member, is indispensable for the transcription of pro-inflammatory genes. Therefore, inhibiting BRD4 may be a prospective therapeutic approach for modulating the inflammatory response and regulating the course of MS. dBET1, a newly synthesized proteolysis-targeting chimera (PROTAC), exhibits effectively degrades of BRD4. However, the precise effects of dBET1 on MS require further investigation. Therefore, we assessed the effect of dBET1 in experimental autoimmune encephalomyelitis (EAE), a typical MS experimental model. Our findings revealed that BRD4 is mainly expressed in astrocytes and neurons of the spinal cords, and is up-regulated in the spinal cords of EAE mice. The dBET1 attenuated lipopolysaccharide-induced expression of astrocytic pro-inflammatory mediators and inhibited deleterious molecular activity in astrocytes. Correspondingly, dBET1, used in preventive and therapeutic settings, alleviated the behavioral symptoms in EAE mice, as demonstrated by decreased demyelination, alleviated leukocyte infiltration, reduced microglial and astrocyte activation, and diminished inflammatory mediator levels. In addition, dBET1 corrected the imbalance in peripheral T cells and protected blood-brain barrier integrity in EAE mice. The underlying mechanism involved suppressing the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase /extracellular signal-regulated kinase, and nuclear factor kappa B pathways. In summary, our data strongly suggests that dBET1 is a promising treatment option for MS.

Understanding the role of BRD8 in human carcinogenesis.

The bromodomain is a conserved protein-protein interaction module that functions exclusively to recognize acetylated lysine residues on histones and other proteins. It is noteworthy that bromodomain-containing proteins are involved in transcriptional modulation by recruiting various transcription factors and/or protein complexes such as ATP-dependent chromatin remodelers and acetyltransferases. Bromodomain-containing protein 8 (BRD8), a molecule initially recognized as skeletal muscle abundant protein and thyroid hormone receptor coactivating protein of 120 kDa (TrCP120), was shown to be a subunit of the NuA4/TIP60-histone acetyltransferase complex. BRD8 has been reported to be upregulated in a subset of cancers and implicated in the regulation of cell proliferation as well as in the response to cytotoxic agents. However, little is still known about the underlying molecular mechanisms. In recent years, it has become increasingly clear that the bromodomain of BRD8 recognizes acetylated and/or nonacetylated histones H4 and H2AZ, and that BRD8 is associated with cancer development in both a NuA4/TIP60 complex-dependent and -independent manner. In this review, we will provide an overview of the current knowledge on the molecular function of BRD8, focusing on the biological role of the bromodomain of BRD8 in cancer cells.

Bromodomain Protein Inhibition Protects ß-Cells from Cytokine-Induced Death and Dysfunction via Antagonism of NF-κB Pathway.

Cytokine-induced ß-cell apoptosis is a major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding its underlying mechanisms, few drugs have been translated to protect ß-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (bromo- and extra-terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in an NOD (non-obese diabetes) mouse model of T1D. However, the effect of BET protein inhibition on ß-cell function in response to cytokines is unknown. Here, we demonstrate that I-BET, a BET protein inhibitor, protected ß-cells from cytokine-induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced ß-cell apoptosis, suggesting a cytoprotective function. Mechanistically, I-BET treatment inhibited cytokine-induced NF-kB signaling and enhanced FOXO1-mediated anti-oxidant response in ß-cells. RNA-Seq analysis revealed that I-BET treatment also suppressed pathways involved in apoptosis while maintaining the expression of genes critical for ß-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting ß-cells from cytokine-induced dysfunction and apoptosis, and targeting BET proteins could have potential therapeutic value in preserving ß-cell functional mass in T1D.

Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 (TcBDF2) using a fluorescence polarization-based high-throughput assay.

Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.

Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage.

Under subarachnoid hemorrhage (SAH) conditions, astrocytes undergo a marked intensification of glycolytic activity, resulting in the generation of substantial amounts of lactate to maintain the energy demand for neurons and other brain cells. Lactate has garnered increasing attention in recent years because of its emerging role in critical biological processes such as inflammation regulation and neuroprotection, particularly through its histone lactylation. Bromodomain-containing protein 4 (BRD4) plays a crucial role in maintaining neural development and promoting memory formation in the central nervous system. Nonetheless, the function and regulatory mechanism of BRD4 and histone lactylation in astrocytes following SAH remain elusive. Our findings indicate that BRD4, a crucial epigenetic regulator, plays a definitive role in histone lactylation. Both in vitro and in vivo, these results demonstrated that targeted silencing of BRD4 in astrocytes can significantly reduce H4K8la lactylation, thereby aggravating the A1 polarization of astrocytes and ultimately affecting the recovery of neural function and prognosis in mice after SAH. In summary, BRD4 plays a pivotal role in modulating astrocyte polarization following SAH via histone lactylation. Targeting this mechanism might offer an efficient therapeutic strategy for SAH.

Epilepsy as a Novel Phenotype of BPTF-Related Disorders.

BACKGROUND: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. METHODS: We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. RESULTS: We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. CONCLUSIONS: Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.

Unlocking cellular plasticity: enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation.

The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for induced pluripotent stem cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small-molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition during iPSC formation. This transition is characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.

BET activity plays an essential role in control of stem cell attributes in Xenopus.

Neural crest cells are a stem cell population unique to vertebrate embryos that retains broad multi-germ layer developmental potential through neurulation. Much remains to be learned about the genetic and epigenetic mechanisms that control the potency of neural crest cells. Here, we examine the role that epigenetic readers of the BET (bromodomain and extra terminal) family play in controlling the potential of pluripotent blastula and neural crest cells. We find that inhibiting BET activity leads to loss of pluripotency at blastula stages and a loss of neural crest at neurula stages. We compare the effects of HDAC (an eraser of acetylation marks) and BET (a reader of acetylation) inhibition and find that they lead to similar cellular outcomes through distinct effects on the transcriptome. Interestingly, loss of BET activity in cells undergoing lineage restriction is coupled to increased expression of genes linked to pluripotency and prolongs the competence of initially pluripotent cells to transit to a neural progenitor state. Together these findings advance our understanding of the epigenetic control of pluripotency and the formation of the vertebrate neural crest.

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.

The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.

Repositioning of Small Molecules through the Inverse Virtual Screening in silico Tool: Case of Benzothiazole-Based Inhibitors of Soluble Epoxide Hydrolase (sEH).

Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole-based compounds was re-investigated by IVS. Four items, originally synthesized and tested on bromodomain-containing protein 9 (BRD9) but yielding poor binding, were critically re-analyzed, disclosing only a partial fit with 3D structure-based pharmacophore models, which, in the meanwhile, were developed for this target. Afterwards, these compounds were re-evaluated through IVS on a panel of proteins involved in inflammation and cancer, identifying soluble epoxide hydrolase (sEH) as a putative interacting target. Three items were subsequently confirmed as able to interfere with sEH activity, leading to inhibition percentages spanning from 70 % up to 30 % when tested at 10 µM. Finally, one benzothiazole-based compound emerged as the most promising inhibitor featuring an IC50 in the low micromolar range (IC50=6.62±0.13 µM). Our data confirm IVS as a predictive tool for accelerating the target identification and repositioning processes.

The Pseudo-Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2.

Phenotypic assays detect small-molecule bioactivity at functionally relevant cellular sites, and inherently cover a variety of targets and mechanisms of action. They can uncover new small molecule-target pairs and may give rise to novel biological insights. By means of an osteoblast differentiation assay which employs a Hedgehog (Hh) signaling agonist as stimulus and which monitors an endogenous marker for osteoblasts, we identified a pyrrolo[3,4-g]quinoline (PQ) pseudo-natural product (PNP) class of osteogenesis inhibitors. The most potent PQ, termed Tafbromin, impairs canonical Hh signaling and modulates osteoblast differentiation through binding to the bromodomain 2 of the TATA-box binding protein-associated factor 1 (TAF1). Tafbromin is the most selective TAF1 bromodomain 2 ligand and promises to be an invaluable tool for the study of biological processes mediated by TAF1(2) bromodomains.

BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.