Abstract 4549: CDK2 inhibition causes anaphase catastrophe through the centrosomal protein CP110

Abstract

Abstract Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Whether aneuploidy is an anti-neoplastic target remains to be learnt. We previously uncovered an unrecognized consequence of Cdk2 inhibition that causes lung cancer cells to undergo anaphase catastrophe, growth inhibition and apoptosis. Cells with activating KRAS mutations were especially sensitive to Cdk2 inhibition. The mechanism of Cdk2-mediated anaphase catastrophe and how activated KRAS promotes this effect was the subject of this study. Live-cell imaging provided direct evidence that after Cdk2 inhibition, lung cancer cells develop multipolar anaphase, undergo multipolar cell division, and the fate of the progeny of these divisions is apoptosis and death. The centrosomal protein CP110, a Cdk2 target protein, was found to be a critical mediator of Cdk2-inhibition-driven anaphase catastrophe. Intriguingly, siRNA-mediated CP110 repression induced anaphase catastrophe of lung cancer cells. By contrast, overexpression of CP110 antagonized anaphase catastrophe caused by Cdk2 inhibition. Furthermore, we found that activated KRAS mutations sensitized lung cancer cells to Cdk2 inhibition by deregulating CP110 expression. Immunohistochemical examination of a paired normal-malignant lung cancer tissue array revealed a statistically significant upregulation of CP110 in lung cancers as compared with normal lung tissues. Notably, CP110 expression was reduced in smokers where KRAS mutations are frequently present. Taken together, this study presents a CP110-dependent pathway that engages anaphase catastrophe in lung cancer cells. It also provides a mechanistic explanation that lung cancers and potentially other cancers with activated KRAS mutation are more sensitive to Cdk2 inhibition due to CP110 deregulation. Citation Format: Shanhu Hu, Alexey V. Danilov, Kristina M. Godek, Bernardo Orr, Laura J. Tafe, Vincent A. Memoli, Fabrizio Galimberti, Saranya Ravi, Andrew J. DeCastro, Yun Lu, Lisa Maria Mustachio, David J. Sekula, Angeline S. Andrew, Sarah J. Freemantle, Duane A. Compton, Ethan Dmitrovsky. CDK2 inhibition causes anaphase catastrophe through the centrosomal protein CP110. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4549. doi:10.1158/1538-7445.AM2014-4549