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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Obstetrics and Gynecology, University of Miami Miller School of Medicine, Miami, Florida. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Karina E
KE
Hew
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
Philip C
PC
Miller
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
Dorraya
D
El-Ashry
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Jun
J
Sun
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Alexandra H
AH
Besser
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida.
Tan A
TA
Ince
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
Mengnan
M
Gu
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
Zhi
Z
Wei
Wistar Institute, Philadelphia, Pennsylvania.
Gao
G
Zhang
Wistar Institute, Philadelphia, Pennsylvania.
Patricia
P
Brafford
Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas.
Wei
W
Gao
Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas.
Yiling
Y
Lu
Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas.
Gordon B
GB
Mills
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. fiona.simpkins@uphs.upenn.edu jslingerland@med.miami.edu.
Joyce M
JM
Slingerland
Department of Obstetrics and Gynecology, University of Miami Miller School of Medicine, Miami, Florida. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania. fiona.simpkins@uphs.upenn.edu jslingerland@med.miami.edu.
Fiona
F
Simpkins
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D011960:Receptors, Estrogen / Q000378:metabolism; D059467:Transcriptome; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D001562:Benzimidazoles; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases