Pharmacological inhibition of BMI1 exerts antitumor effect on MYCN-amplified neuroblastoma with activation of the p53 pathway

BMI1, a constituent of the Polycomb Repressive Complex 1 (PRC1), has been identified as overexpressed in a variety of cancers, including neuroblastoma, highlighting its potential as a viable target for cancer therapeutics. Given its pivotal role, a number of BMI1 inhibitors have been synthesized and assessed for their therapeutic efficacy across a spectrum of cancers in recent years. This investigation demonstrates that the BMI1 inhibitors PTC-028 and PTC-209 exhibit selective antitumor activities against MYCN-amplified neuroblastoma. Notably, PTC-028, which exhibits toxicity at lower concentrations, triggers apoptosis in neuroblastoma cells, promotes G1 phase accumulation, and reduces S phase cell populations, thereby inducing cell cycle arrest. A thorough examination utilizing RNA sequencing has unveiled that treatment with PTC-028 activates the p53 signaling pathway, suggesting its critical involvement in the mechanism of cell death induction. Moreover, PTC-028 treatment leads to a decrease in the protein levels of anti-apoptotic factors, including BCL2 and MCL1. Significantly, PTC-028 has also demonstrated antitumor efficacy in a mouse xenograft model of human neuroblastoma cells. Consequently, BMI1 inhibitors, especially PTC-028, emerge as promising therapeutic agents for the management of aggressive MYCN-amplified neuroblastomas.