Inactivation of the Mitogen-Activated Protein Kinase Pathway as a Potential Target-Based Therapy in Ovarian Serous Tumors with KRAS or BRAF Mutations

Abstract

Activation of mitogen-activated protein kinase (MAPK) occurs in response to various growth stimulating signals and as a result of activating mutations of the upstream regulators, KRAS and BRAF, which can be found in many types of human cancer. To investigate the roles of MAPK activation in tumors harboring KRAS or BRAF mutations, we inactivated MAPK in ovarian tumor cells using CI-1040, a compound that selectively inhibits MEK, an upstream regulator of MAPK and thus prevents MAPK activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated tumor cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. Long serial analysis of gene expression identified several differentially expressed genes in CI-1040-treated MPSC1 cells harboring an activating mutation in BRAF (V599L). The most striking changes were down-regulation of cyclin D1, COBRA1, and transglutaminase-2 and up-regulation of tumor necrosis factor-related apoptosis-induced ligand, thrombospondin-1, optineurin, and palladin. These patterns of gene expression were validated in other CI-1040-treated tumor cells based on quantitative PCR. Constitutive expression of cyclin D1 partially reversed the growth inhibitory effect of CI-1040 in MPSC1 cells. Our findings indicate that an activated MAPK pathway is critical in tumor growth and survival of ovarian tumors with KRAS or BRAF mutations and suggest that the CI-1040 induced phenotypes depend on the mutational status of KRAS and

Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor

“…This finding is consistent with our recent study showing that activated MAPK pathway is critical for tumor growth only in tumors harboring KRAS or BRAF mutations but not in tumors with wild-type KRAS and BRAF genes. 39 More interestingly, we observed a profound reduction of cell motility in CI-1040-and PD98059-treated IST-2 cells as evidenced by both wound assay and time-lapse videomicroscopy analysis. The lack of inhibitory effects of MEK inhibitors on motility and invasion in normal EVT cells is consistent with the fact that normal EVT cells do not express activated MAPK.…”

“…39 Likewise, PD98059 is another MEK inhibitor and has been used in many reports to study the MAPK activation. Like PSTTs, IST-2 cells in culture expressed activated MAPK.…”

KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer

“…Activation of ERK1/2 in turn activates downstream cellular targets (Peyssonnaux and Eychene, 2001;Allen et al, 2003) including a variety of cellular and nuclear proteins. Although the functions of the RAS -RAF -MEK -ERK pathway and its downstream effectors have been recently explored, only the serous type of ovarian cancer has been studied (Hsu et al, 2004;Pohl et al, 2005). In addition, the biological role of this pathway in the development of ovarian cancers of other histological types is unknown.…”

Mutant BRAF Induces DNA Strand Breaks, Activates DNA Damage Response Pathway, and Up-Regulates Glucose Transporter-1 in Nontransformed Epithelial Cells

“…8 Activating mutations in BRAF and KRAS appear to exert equivalent tumorpromoting effects as based on the mutual exclusive mutation in both genes. 5,9 Constitutive activation of BRAF due to V600E mutation activates the MAPK pathway and results in up-regulation of several genes with tumor-promoting functions including cyclin D1, 10,11 and targeting BRAF and its downstream effectors has emerged as a new therapeutic strategy for those tumors harboring the BRAF mutation. [12][13][14][15][16] Ovarian low-grade serous tumor represents a unique type of ovarian epithelial neoplasm and is distinct from ovarian high-grade serous carcinoma, the conventional type of ovarian cancer, based on their clinical, pathological, and molecular features.…”

“…22 Moreover, BRAF and KRAS mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer. 11,23 Interestingly, BRAF or KRAS mutations can be detected in morphologically normal-appearing cyst epithelium that is adjacent to a serous borderline tumor but not in the cystadenomas without concurrent borderline tumors, suggesting the mutations may occur early during tumor progression of ovarian low-grade serous tumors. 24 Although the oncogenic roles of BRAF mutations have been established in mouse models, 25 it remains largely unclear what are the biological effects of BRAF mutations in the very beginning of tumor formation such as in nontransformed epithelial cells.…”