Synthetic Lethality of Retinoblastoma Mutant Cells in the Drosophila Eye by Mutation of a Novel Peptidyl Prolyl Isomerase Gene

Kyle A. Edgar^*^,1, Marcia Belvin^*^,1^,2^,3, Annette L. Parks^*^,4, Kellie Whittaker^*, Matt B. Mahoney^*^,5, Monique Nicoll^*, Christopher C. Park^*^,6, Christopher G. Winter^*, Feng Chen^*^,7, Kim Lickteig^*^,8, Ferhad Ahmad^*, Hanife Esengil^*^,9, Matthew V. Lorenzi, Amanda Norton^*^,10, Brent A. Rupnow, Laleh Shayesteh^*, Mariano Tabios^*, Lynn M. Young^*^,11, Pamela M. Carroll^,12, Casey Kopczynski^*^,13, Gregory D. Plowman^*^,3, Lori S. Friedman^*^,3 and Helen L. Francis-Lang^*

^* Exelixis, South San Francisco, California 94083
Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543
Applied Genomics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543

^² Corresponding author: Genentech, 1 DNA Way, Bldg. 11, MS215, South San Francisco, CA 94080.
E-mail: mbelvin{at}gene.com

Mutations that inactivate the retinoblastoma (Rb) pathway arecommon in human tumors. Such mutations promote tumor growthby deregulating the G1 cell cycle checkpoint. However, uncontrolledcell cycle progression can also produce new liabilities forcell survival. To uncover such liabilities in Rb mutant cells,we performed a clonal screen in the Drosophila eye to identifysecond-site mutations that eliminate Rbf^– cells, but allowRbf⁺ cells to survive. Here we report the identification ofa mutation in a novel highly conserved peptidyl prolyl isomerase(PPIase) that selectively eliminates Rbf^– cells from theDrosophila eye.