The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Abstract

Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…The SLIs revealed in cancer cell lines or mouse models may not be reproducible in actual tumor tissues due to heterogeneity or microenvironmental factors. [293][294][295] More rigorous validation using patient-derived organoids and PDX models is required. Besides, off-target toxicity and lack of biomarker-based patient stratification hamper successful clinical application.…”

“…First, the clinical translation efficiency of SL targets and drug candidates identified by high‐throughput screens is still relatively low. The SLIs revealed in cancer cell lines or mouse models may not be reproducible in actual tumor tissues due to heterogeneity or microenvironmental factors 293–295 . More rigorous validation using patient‐derived organoids and PDX models is required.…”

Epigenetic regulation in cancer

“…Initial small‐molecule BET inhibitors, exemplified by JQ1, were instrumental in elucidating the oncogenic role of BET proteins and the consequent effects of BET inhibition on the expression of various oncogenes. This modulation of key oncogenes is believed to underlie the antitumorigenic properties of BET inhibitors observed in preclinical models 268,269 . Nonetheless, the clinical application of these agents has been constrained by their suboptimal pharmacokinetic profiles, including a brief half‐life and limited oral bioavailability.…”

“…This modulation of key oncogenes is believed to underlie the antitumorigenic properties of BET inhibitors observed in preclinical models. 268 , 269 Nonetheless, the clinical application of these agents has been constrained by their suboptimal pharmacokinetic profiles, including a brief half‐life and limited oral bioavailability. In triple‐negative breast cancer, BET inhibitors such as JQ1 and I‐BET151 have shown efficacy in countering resistance to tyrosine kinase inhibitors, notably lapatinib.…”

A low-cost voltammetric sensor based on multi-walled carbon nanotubes for highly sensitive and accurate determination of nanomolar levels of the anticancer drug Ribociclib in bulk and biological fluids

“…5 These inhibitors work by specifically targeting the overactive CDK4/6 within cancerous cells, effectively halting the cell cycle and impeding their rapid proliferation. 6 Ribociclib (LEE011, RIBO) is a highly specific, orally bioavailable, small-molecule inhibitor of CDK4 and CDK6. 7 In 2017, the United States Food and Drug Administration approved the utilization of Ribociclib in conjunction with an aromatase inhibitor, such as letrozole, to address breast cancer in postmenopausal women characterized by hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative status, particularly in advanced or metastatic stages.…”