The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.

Optimized transcriptional signature for evaluation of MEK/ERK pathway baseline activity and long-term modulations in ovarian cancer

“…Expression of the MPAS gene signature is associated with MEK/ERK pathway activity across various tumors (29). Therefore, we used it to confirm MEK/ERK inhibition by trametinib in ovarian cancer (18). Most MPAS genes displayed prominent downregulation in response to trametinib, but two genes ( DUSP6 and CCND1 ) displayed inconsistent results, and EPHA4 expression levels were below reliable levels of detection.…”

“…However, recent analyses of accumulated genomic data revealed that HGSOC, while rarely harboring KRAS/BRAF mutations, still often displays amplifications and overexpression of MEK1/2 pathway elements (16). High MEK1/2 activity was experimentally confirmed in HGSOC cell lines and clinical samples and identified as a negative prognostic factor (17,18). MEK1/2 activation occurs in response to cisplatin and may render tumors resistant to platinum treatment (18)(19)(20).…”

“…High MEK1/2 activity was experimentally confirmed in HGSOC cell lines and clinical samples and identified as a negative prognostic factor (17,18). MEK1/2 activation occurs in response to cisplatin and may render tumors resistant to platinum treatment (18)(19)(20). Moreover, the MEK1/2 pathway affects the subpopulation of chemoresistant ovarian cancer stem-like cells (CSCs) defined by high ALDH1 levels (18,(21)(22)(23).…”

“…High MPAS was associated with higher sensitivity to MEK1/2 inhibition by cobimetinib in multiple malignant cell lines, increased response to the BRAF inhibitor vemurafenib in BRAF V600 -positive melanoma patients, and negative survival prognosis. Earlier we successfully utilized MPAS genes to confirm MEK1/2-ERK1/2 pathway inhibition by trametinib in HGSOC cell lines and xenografts (18). In the present study, we aimed to further refine the MPAS gene signature and improve its efficiency in HGSOC by functionally linking MEK1/2-ERK1/2 activity to background levels of MPAS genes and changes, using HGSOC cell lines and patient samples from The Cancer Genome Atlas database.…”

Cryptocaryone Promotes ROS-Dependent Antiproliferation and Apoptosis in Ovarian Cancer Cells

“…Human OVCA line (SKOV3), purchased from ATCC (Manassas, VA, USA), was cultured in McCoy’s 5A medium (Sigma-Aldrich; St. Louis, MO, USA) containing 10% fetal bovine serum (FBS). Human Type I OVCA cell lines (TOV-21G and TOV-112D) [ 32 ], purchased from Bioresource Collection and Research Center (BCRC) (Hsinchu, Taiwan), were cultured in (MCDB105/Medium 199 1:1) medium (Gibco, Grand Island, NY, USA) containing 15% FBS. These cell cultures were supplemented with 100 U/mL penicillin and 100 μg/mL streptomycin.…”