SYNTHETIC LETHAL INTERACTION BETWEEN TUMOR SUPPRESSOR RAD17 AND CHK1 KINASE IN HUMAN CANCER CELLS
John Shen, Kate Licon, Ana Bojorquez-Gomez, Lucy Xu, Huwate Yeernas, Trey Ideker.
University of California, San Diego, La Jolla, CA.
Cancer cells often have impaired tumor suppressors. Although current drugs can target cells with gain-of-function oncogenes, targeting cells with loss-of-function tumor suppressors is problematic. However, performing synthetic lethal (SL) screens for proteins that are essential only in the context of specific cancer-causing alterations can reveal “druggable” proteins within cells that have "undruggable" genetic alterations. Two proteins are SL if the loss of either one is viable to the cell, but the suppression of both is lethal to the cell. So, targeting a protein that is SL to tumor suppressors should destroy only cancer cells that have altered tumor suppressors and spare normal cells. This study elucidates such SL interactions of Rad17, a tumor suppressor, and Chek1 kinase (Chk1) in humans. We find that cells that have loss-of-function of Rad17 exhibit sensitivity to suppression of the Chk1 kinase. We also find that the mechanism underlining the Rad17-Chk1 SL interaction seems to be P53 dependent, but cell cycle independent.