Aimee L. Jackson^*1, Mao Mao^*1, Sumire Kobayashi¹, Teresa Ward¹, Matthew Biery¹, Hongyue Dai¹, Steven R. Bartz² and Peter S. Linsley¹

¹Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck and Co., Inc., Seattle, WA 98109. ²Sirna Therapeutics, a wholly-owned subsidiary of Merck and Co., Inc., San Francisco, CA 94158.

^*These two authors contributed equally to this work.

Abstract

We identified gene expression signatures predicting responsiveness to a Kinesin-5 (KIF11) inhibitor (Kinesin-5i) in cultured colon tumor cell lines. Genes predicting resistance to Kinesin-5i were enriched for those from chromosome 20q, a region of frequent amplifi cation in a number of tumor types. siRNAs targeting genes in this chromosomal region identified AURKA, TPX2 and MYBL2 as genes whose disruption enhances response to Kinesin-5i. Taken together, our results show functional interaction between these genes, and suggest that their overexpression is involved in resistance to Kinesin-5i. Furthermore, our results suggest that patients whose tumors overexpress AURKA due to amplification of 20q will more likely resist treatment with Kinesin-5 inhibitor, and that inactivation of AURKA may sensitize these patients to treatment.