MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model

Abstract

Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is ERK. PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR-ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of four CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Further, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss, severe skin peeling) at high doses. Our findings indicate that the MEK/ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC.

Predicting time to ovarian carcinoma recurrence using protein markers

“…STAT5α, pMEK1, and pPKCα proteins, which are representative markers of 3 intracellular signaling (STAT signaling, PKC signaling, and MEK/ERK signaling) pathways, play especially important roles associated with cell proliferation, survival, and cell invasion in cancer cells and the activation of these signaling pathways would be expected to be associated with shorter PFS/OS time in patients with ovarian cancer. Although inhibition of EGFR has not shown clear efficacy in treatment of ovarian carcinoma (32), MEK inhibitors have been reported to control low-grade disease, and combination therapy may provide a possible avenue toward improving outcome of patients with ovarian cancer (33,34).…”

Phosphorylation is the switch that turns PEA-15 from tumor suppressor to tumor promoter

“…In ovarian clear cell carcinoma, Ser116 phosphorylation renders cells more sensitive to selumetinib, a selective inhibitor of the MEK1/2 kinase. 36 Selumetinib treatment upregulated PEA-15 phosphorylation at Ser116 in RMG-I, but not in OVTOKO ovarian clear cell carcinoma lines. Interestingly, both selumetinib sensitivity and PEA-15 phosphorylation correlated with EGFR expression in these cells.…”

Histone Deacetylase Inhibitor Enhances the Efficacy of MEK Inhibitor through NOXA-Mediated MCL1 Degradation in Triple-Negative and Inflammatory Breast Cancer

“…While ERK inhibitors have not been effective in clinical testing, compounds that inhibit MEK (an upstream activator of ERK) including selumetinib (formerly AZD6244) (23,24), and the more potent compound pimasertib (formerly AS703026, EMD Serono, Inc., Rockland, MA) (25,26) have displayed clinical activity in phase II trials for melanoma and ovarian cancer (27,28). While the effectiveness of these compounds remains to be clinically established in breast cancer, we have previously shown their potential for preventing metastasis in preclinical xenograft models of TNBC (29).…”