SRA515

D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.

In conclusion, these results suggested that AZD5153 might be an excellent GEM sensitizer in pancreatic cancer.

Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.

We highlight the promising results of the clinical trial involving the combination of adavosertib and irinotecan, which encourages further clinical trials with adavosertib targeting NB with ATRX mutations. Preclinical results with BET inhibitors (OTX015 and AZD5153) and with 6-thio-2'-deoxyguanosine, targeting NB with TERT mutations, are promising. Both represent future therapeutic targets, emphasizing the need to prioritize research using these models.

Our results provide the first lipid metabolism-based gene signature for predicting the survival of patients with DLBCL. Furthermore, by determining novel subtypes with our lipid metabolism prognostic model we illustrated that drugs that compromising MYC target genes rather than immune checkpoint inhibitors may be beneficial to DLBCL patients with certain lipid metabolism profiles.

Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.

This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.

Methods Single-cell RNA sequencing (scRNA-seq) was performed in Phase II clinical trial of pembrolizumab (anti-Programmed cell death 1(PD-1)) in hepatitis B virus-related HCC patients ( NCT03419481 ). Notably, a clinically-trialed BRD4 specific inhibitor AZD5153 synergized with PD-L1 antibody to suppress tumor growth and ameliorated immunosuppressive microenvironment, which was accompanied by significant reduction and increase in MaVEC and LEC densities, respectively. Conclusions Our data demonstrated that epigenetic reversion of LEC-to-MaVEC trans-differentiation by BRD4 inhibition may be a potential strategy for improving HCC immunotherapy.

Adding IFNß1 to cells treated with acalabrutinib partially rescued PAX5 activation. Our results demonstrate AZD5153 enhances the efficacy of acalabrutinib through PAX5 and BCR mechanisms that are critical for ABC-DLBCL.

Treatment with PROTAC ARV825 that degrades BET proteins, resulted in similar growth inhibitory effects...Combination treatments of BETi+topotecan/ifosfamide indicated that AZD5153 potentiated the anti-cancer effect of salvage therapy in TT2 OS PDX, was well tolerated, and increased the probability of survival in mice. Efficacy in an OS RS+ metastatic lesion model is in progress. These data collectively suggest that BET inhibition as a single agent and in combination with low-dose salvage therapy holds promise as novel treatment strategies for inducing RS-mediated cell death in aggressive OS.

To solve this problem, we found that BRD4 inhibitor AZD5153 and PARP inhibitor olaparib had a widespread synergistic effect in multiple models with different gene backgrounds. The similar results of these models further proved that the mechanism identified was consistent with the biological process occurring in ovarian cancer patients after drug treatment. This consistency between the results of different models suggests the possibility of translating these laboratory research findings into clinical studies towards developing treatments.

We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. Genes such as ADGRA2, MYB, TNFRSF11A, S100A10, PLEKHH3, DHRS2 and FOXP1-AS1 were identified as possible key regulators. Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature.