TY - JOUR
T1 - A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma
AU - Puyol, Marta
AU - Martín, Alberto
AU - Dubus, Pierre
AU - Mulero, Francisca
AU - Pizcueta, Pilar
AU - Khan, Gulfaraz
AU - Guerra, Carmen
AU - Santamaría, David
AU - Barbacid, Mariano
N1 - Funding Information:
We thank M. Cañamero for advice on histology and immunhistochemistry and M.C. González, M. San Román, and R. Villar for technical assistance. We also thank D.W. Owens (Global Research & Development, Pfizer Inc.) for a generous gift of PD0332991. This work was supported by grants from the Ministry of Science and Innovation (MICINN) (SAF2006-11773 and CSD2007-00017), Autonomous Community of Madrid (GR/SAL/0587/2004 and S2006/BIO-0232), Fundación de la Mutua Madrileña and EU-Framework Programme (LSHG-CT-2007-037665) to M.B. D.S. received support from Fondo de Investigación Sanitaria (PI061631), P.D. from INSERM and Association pour la Recherche contre le Cancer (Région Aquitaine), and C.G. from Fondo de Investigación Sanitaria (PI042124) and Autonomous Community of Madrid (GR/SAL/0349/2004).
PY - 2010/7
Y1 - 2010/7
N2 - We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes.
AB - We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes.
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U2 - 10.1016/j.ccr.2010.05.025
DO - 10.1016/j.ccr.2010.05.025
M3 - Article
C2 - 20609353
AN - SCOPUS:77954279920
SN - 1535-6108
VL - 18
SP - 63
EP - 73
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -