KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian 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 (Po0.001), and p-ERK1/2 (Po0.001). 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 ¼ 0.2460, P ¼ 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.

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

“…Profound growth inhibition and apoptosis were observed in CI-1040-treated ovarian cancer cells with mutations in either KRAS or BRAF, compared with ovarian cancer cells containing wild-type KRAS/BRAF. 39 Although KRAS-mutated lung cancers, which comprise 20-30% of non-small cell lung cancers, are known not to respond to targeted therapies, recently it was shown that the combination of PI3K and MEK inhibitors may be a very potent combination in the treatment of KRAS-mutated lung cancers. When mouse models of lung cancer driven by mutant KRAS were treated with a combination of pan-PI3K, a mammalian target of rapamycin inhibitor, and an MEK inhibitor, there was marked synergy in shrinking these tumors.…”

A classification system for clinical relevance of somatic variants identified in molecular profiling of cancer

“…9 Meanwhile, these variants are the active subjects of clinical trials with MEK inhibitors in ovarian cancers. 29 Similarly, the p.Val600Glu variant of BRAF is druggable in melanoma, 12,30,31 whereas recent evidence indicates its potential predictive utility in colorectal cancer patients treated with EGFR inhibitors. 32 Figure 3 shows in further detail how sequence variants were classified for each of the four primary sites of cancer in our study.…”

MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

“…The results of a phase III study have demonstrated that GSK1120212 is associated with a significant improvement in progression-free survival and overall survival, compared with chemotherapy, in patients with V600E or V600K BRAF-mutated advanced melanoma (23). Several studies have shown that KRAS and/ or BRAF mutations are associated with the sensitivity to MEK inhibitors in melanoma, thyroid cancer, colon cancer, and ovarian cancer (23)(24)(25)(26)(27). However, very limited information is available about the somatic MEK1 mutations in human malignancies.…”