RRC ID 43524
Author Nakayama N, Nakayama K, Yeasmin S, Ishibashi M, Katagiri A, Iida K, Fukumoto M, Miyazaki K.
Title KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer.
Journal Br J Cancer
Abstract This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II (P<0.001), and p-ERK1/2 (P<0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P=0.2460, P=0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. Cl-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.
Volume 99(12)
Pages 2020-8
Published 2008-12-16
DOI 10.1038/sj.bjc.6604783
PII 6604783
PMID 19018267
PMC PMC2607229
MeSH Animals Base Sequence Cell Line, Tumor Cell Proliferation Enzyme Activation Female Humans Mice Mice, Nude Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors Mitogen-Activated Protein Kinase 3 / metabolism Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors* Mitogen-Activated Protein Kinase Kinases / metabolism Mutation / genetics Ovarian Neoplasms / enzymology* Ovarian Neoplasms / genetics* Ovarian Neoplasms / pathology Phosphorylation Prognosis Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins B-raf / genetics* Proto-Oncogene Proteins B-raf / metabolism Proto-Oncogene Proteins p21(ras) Substrate Specificity Survival Rate Xenograft Model Antitumor Assays ras Proteins / genetics* ras Proteins / metabolism
IF 5.416
Times Cited 60
Human and Animal Cells