The bromodomain-containing protein 9 (BRD9) was identified as a key molecule in the progression of gastrointestinal stromal tumors (GISTs), according to researchers from the Hospital of Jilin University, Changchun, China. The study was published in the journal Cell Death & Disease.
BRD9 inhibition can be considered as a new therapeutic strategy in GISTs, used as either stand-alone therapy or in combination with imatinib mesylate, the authors said.
“The results demonstrated that the combination of imatinib and BRD9 inhibition promotes effective cellular apoptosis due to AKT inhibition, leading to GSK-3β/NF-κB activation and resulting in [p53-upregulated modulator of apoptosis (PUMA)] induction, thus achieving better antitumor activity with increased apoptosis and reduced cellular proliferation,” they said.
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Mu et al found that BRD9 was upregulated in GIST specimens. The comparison was established by the analysis of 38 clinically confirmed GIST tissues and 25 adjacent nontumor tissues.
They observed a correlation between positive staining of BRD9 and tumor size. They also found the positive staining of BRD9 to be correlated with the grade of risk, but not with gender, age, or tumor location.
BRD9 downregulation or inhibition impaired tumor cells’ proliferation while enhancing apoptosis. In addition, the authors showed that the inhibition of BRD9 enhanced imatinib activity in GIST both in vitro and in vivo.
The inhibition occurred via upregulation of PUMA-dependent apoptosis. Mechanistic studies showed that BRD9 promotes PUMA activation through the TUFT1/AKT/GSK-3β/p65 axis, and PUMA is upregulated by imatinib by targeting the AKT/GSK-3β/p65 axis.
Imatinib is a tyrosine kinase inhibitor currently used as a standard first-line drug for patients with GIST. However, its use has been associated with the development of secondary drug resistance, which limits the success of the therapeutics. Hence, the search for novel targeted therapeutics is still a major focus of the research community.
Mu J, Sun X, Zhao Z, Sun H, Sun P. BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors. Cell Death Dis. 2021;12(11):962. doi:10.1038/s41419-021-04186-6