MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer

• Published in: Clinical cancer research 2016-02, Vol.22 (4), p.935-947
• Main Authors: Hew, Karina E, Miller, Philip C, El-Ashry, Dorraya, Sun, Jun, Besser, Alexandra H, Ince, Tan A, Gu, Mengnan, Wei, Zhi, Zhang, Gao, Brafford, Patricia, Gao, Wei, Lu, Yiling, Mills, Gordon B, Slingerland, Joyce M, Simpkins, Fiona
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzimidazoles - administration & dosage; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Estradiol - administration & dosage; Estradiol - analogs & derivatives; Estrogen Receptor Modulators - pharmacology; Female; Humans; Kaplan-Meier Estimate; MAP Kinase Signaling System; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinases - metabolism; Neoplasms, Cystic, Mucinous, and Serous - drug therapy; Neoplasms, Cystic, Mucinous, and Serous - enzymology; Neoplasms, Cystic, Mucinous, and Serous - mortality; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - mortality; Receptors, Estrogen - metabolism; Transcriptome; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-15-0534

Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance. Effects of MEKi (selumetinib), antiestrogen (fulvestrant), or both were assayed in ER-positive HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOC datasets with high versus low pMAPK by RPPA were used to generate a "MAPK-activated gene signature." Gene signature components that were reversed by MEKi were then identified. High intratumor pMAPK independently predicts decreased survival (HR, 1.7; CI > 95%,1.3-2.2; P = 0.0009) in 408 HGSOC from The Cancer Genome Atlas. A differentially expressed "MAPK-activated" gene subset was also prognostic. "MAPK-activated genes" in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater antitumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed that dual therapy downregulated DNA replication and cell-cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of "MAPK-activated genes" in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (P = 0.000265) and warrant testing as a signature predictive of MEKi response. High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER-positive HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors.