TY - JOUR
T1 - CDK2 inhibition causes anaphase catastrophe in lung cancer through the centrosomal protein CP110
AU - Hu, Shanhu
AU - Danilov, Alexey V.
AU - Godek, Kristina
AU - Orr, Bernardo
AU - Tafe, Laura J.
AU - Rodriguez-Canales, Jaime
AU - Behrens, Carmen
AU - Mino, Barbara
AU - Moran, Cesar A.
AU - Memoli, Vincent A.
AU - Mustachio, Lisa Maria
AU - Galimberti, Fabrizio
AU - Ravi, Saranya
AU - De Castro, Andrew
AU - Lu, Yun
AU - Sekula, David
AU - Andrew, Angeline S.
AU - Wistuba, Ignacio I.
AU - Freemantle, Sarah
AU - Compton, Duane A.
AU - Dmitrovsky, Ethan
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/5/15
Y1 - 2015/5/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-14-1494
DO - 10.1158/0008-5472.CAN-14-1494
M3 - Article
C2 - 25808870
AN - SCOPUS:84942889240
SN - 0008-5472
VL - 75
SP - 2029
EP - 2038
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -