MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in ER-positive high-grade serous ovarian cancer

Karina E. Hew, Philip C. Miller, Dorraya El-Ashry, Jun Sun, Alexandra H. Besser, Tan A. Ince, Mengnan Gu, Zhi Wei, Gao Zhang, Patricia Brafford, Wei Gao, Yiling Lu, Gordon Mills, Joyce M. Slingerland, Fiona Simpkins

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)935-947
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number4
DOIs
StatePublished - Feb 15 2016
Externally publishedYes

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Estrogen Receptor Modulators
Mitogen-Activated Protein Kinase Kinases
Estrogen Receptors
Ovarian Neoplasms
Protein Array Analysis
Genes
Heterografts
Gene Components
AZD 6244
Atlases
DNA Replication
Neoplasms
Cell Cycle
Estrogens
Research Design
Down-Regulation
Biomarkers
Genome
Breast Neoplasms
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in ER-positive high-grade serous ovarian cancer. / 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; Slingerland, Joyce M.; Simpkins, Fiona.

In: Clinical Cancer Research, Vol. 22, No. 4, 15.02.2016, p. 935-947.

Research output: Contribution to journalArticle

Hew, KE, Miller, PC, El-Ashry, D, Sun, J, Besser, AH, Ince, TA, Gu, M, Wei, Z, Zhang, G, Brafford, P, Gao, W, Lu, Y, Mills, G, Slingerland, JM & Simpkins, F 2016, 'MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in ER-positive high-grade serous ovarian cancer', Clinical Cancer Research, vol. 22, no. 4, pp. 935-947. https://doi.org/10.1158/1078-0432.CCR-15-0534
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 ; Slingerland, Joyce M. ; Simpkins, Fiona. / MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in ER-positive high-grade serous ovarian cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 4. pp. 935-947.
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abstract = "Purpose: 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. Experimental Design: 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.",
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T1 - MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in ER-positive high-grade serous ovarian cancer

AU - Hew, Karina E.

AU - Miller, Philip C.

AU - El-Ashry, Dorraya

AU - Sun, Jun

AU - Besser, Alexandra H.

AU - Ince, Tan A.

AU - Gu, Mengnan

AU - Wei, Zhi

AU - Zhang, Gao

AU - Brafford, Patricia

AU - Gao, Wei

AU - Lu, Yiling

AU - Mills, Gordon

AU - Slingerland, Joyce M.

AU - Simpkins, Fiona

PY - 2016/2/15

Y1 - 2016/2/15

N2 - Purpose: 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. Experimental Design: 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.

AB - Purpose: 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. Experimental Design: 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.

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