CDK2 inhibition causes anaphase catastrophe in lung cancer through the centrosomal protein CP110

Shanhu Hu, Alexey V. Danilov, Kristina Godek, Bernardo Orr, Laura J. Tafe, Jaime Rodriguez-Canales, Carmen Behrens, Barbara Mino, Cesar A. Moran, Vincent A. Memoli, Lisa Maria Mustachio, Fabrizio Galimberti, Saranya Ravi, Andrew De Castro, Yun Lu, David Sekula, Angeline S. Andrew, Ignacio I. Wistuba, Sarah Freemantle, Duane A. ComptonEthan Dmitrovsky

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacologic targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. Mechanisms of CDK2-mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced ana-phase catastrophe of lung cancer cells. In contrast, CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. Thus, CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe. Independent examination of murine and human paired normal-malignant lung tissues revealed marked upregulation of CP110 in malignant versus normal lung. Human lung cancers with KRAS mutations had significantly lower CP110 expression as compared with KRAS wild-type cancers. Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations.

Original languageEnglish (US)
Pages (from-to)2029-2038
Number of pages10
JournalCancer Research
Volume75
Issue number10
DOIs
StatePublished - May 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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