Functional Genetic Screens Identify Genes Essential for Tumor Cell Survival in Head and Neck and Lung Cancer

Purpose: Despite continuous improvement of treatment regimes, the mortality rates for non–small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited. ExperimentalDesign:Wecombinedthedatafromgenome-widesiRNAscreensontumorcelllethalityin a lung and a head and neck cancer cell line. Results: We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2–M phase transition, underlining the importanceofthiscell-cyclecheckpointfortumorcellsurvival.Fivegenesfromthiscluster(CKAP5,KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown ofKIF11(kinesin family member11)were reproducedbyinhibition ofKIF11 using the small-molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment. Conclusion:Thisstudyidentifiedawidearrayofdruggablegenesforbothlungandheadandneckcancer. In particular, multiple genes involved in the G2–M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets. Clin Cancer Res; 19(8); 1994–2003. � 2013 AACR.