Boosting cancer sensitivity to CDK4, CDK6 inhibitors by inhibiting the PRMT5-MDM4 axis
INDICATION: Melanoma; breast cancer; esophageal cancer; pancreatic cancer
Inhibiting the PRMT5-MDM4 axis could increase the sensitivity of melanoma and other cancers to the dual CDK4/CDK6 inhibitor Ibrance palbociclib. In five human melanoma cell lines, resistance to Ibrance was associated with greater sensitivity to the PRMT5 inhibitor GSK3326595. Treatment with GSK3326595 or an shRNA against MDM4, a downstream mediator of PRMT5, raised resistant cells' sensitivity to Ibrance. In a xenograft mouse model of melanoma, Ibrance plus GSK3326595 given before or after the development of Ibrance resistance reduced tumor volume and extended survival. Additionally, the combination decreased tumor volume in xenograft mouse models of breast, esophageal and pancreatic cancers compared with either agent alone...