Assessing Cancer Cell Senescence as a Novel Anti-Cancer Therapy for Pancreatic Cancer

Pancreatic cancer is the deadliest major cancer with a 5-year survival rate of 12%. Current PDAC therapeutics an ineffective and highly toxic, leading to a variety of harsh side effects that greatly reduce patient quality of life. Here, were present a novel treatment strategy for the treatment of PDAC that works by inhibiting VRK1 mediated phosphorylation of BAF. Fixed cell microscopy of VRK1 knockdown cells reveals a distinct nuclear blebbing phenotype and reduction in BAF phosphorylation. Lack of BAF phosphorylation prevents BAF binding to Lamin A, which must also be phosphorylated by Aurora B kinase. Luteolin has been identified as a VRK1 inhibitor that induces this nuclear blebbing phenotype. The development of Luteolin analogues with modification to the B ring structure reveal the importance of 4’ carbon modifications for VRK1 binding. The addition of a tert-butyl group to the 4’ carbon of Luteolin significantly increased its affinity for the VRK1 binding pocket, increasing nuclear blebbing and reducing pBAF expression. Compounds that inhibit either side of this two-sided BAF/Lamin A pathway induce widespread nuclear blebbing, cellular senescence, and anti-tumor immunity. Taken together, these data provide the rationale to pursue EpoAurorin and VRK1 inhibitors as novel therapeutics for the treatment of PDAC.