The Kinase Mirk/dyrk1B: A Possible Therapeutic Target in Pancreatic Cancer

摘要

Pancreatic ductal adenocarcinomas are strongly resistant to chemotherapeutic drugs and radiation, underscoring the need for new therapeutic targets, particularly ones which target the numerous out of cycle cancer cells. Analysis of resected tumors for nuclear Ki67 antigen has shown that about 70% of pancreatic cancer cells are out of cycle, some post-mitotic. Other out of cycle cells are in a quiescent, reversible G0 state, resistant to drugs which target dividing cells, with some able to repopulate a tumor. The serine/threonine kinase Mirk/dyrk1B is a downstream effector of oncogenic K-ras, the most common mutation in this cancer. Mirk expression is elevated in quiescent pancreatic cancer cells and mediates their prolonged survival through increasing expression of a cohort of antioxidant genes. Mirk is expressed in about 90% of pancreatic cancers and is amplified in a subset. Mirk appears not to be an essential gene for normal cells from embryonic knockout studies in mice and RNA interference studies on cultured cells, but is upregulated in pancreatic tumor cells. These unusual characteristics suggest that Mirk may be a selective target for therapeutic intervention.