TY - JOUR
T1 - Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy
AU - Sunaga, Noriaki
AU - Shames, David S.
AU - Girard, Luc
AU - Peyton, Michael
AU - Larsen, Jill E.
AU - Imai, Hisao
AU - Soh, Junichi
AU - Sato, Mitsuo
AU - Yanagitani, Noriko
AU - Kaira, Kyoichi
AU - Xie, Yang
AU - Gazdar, Adi F.
AU - Mori, Masatomo
AU - Minna, John D.
PY - 2011/2
Y1 - 2011/2
N2 - Oncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non - small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS-mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we conducted microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines with and without oncogenic KRAS. We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho - epidermal growth factor receptor, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs.
AB - Oncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non - small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS-mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we conducted microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines with and without oncogenic KRAS. We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho - epidermal growth factor receptor, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs.
UR - http://www.scopus.com/inward/record.url?scp=79951823579&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79951823579&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-10-0750
DO - 10.1158/1535-7163.MCT-10-0750
M3 - Article
C2 - 21306997
AN - SCOPUS:79951823579
SN - 1535-7163
VL - 10
SP - 336
EP - 346
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 2
ER -