Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells

Fiona Simpkins, Kibeom Jang, Hyunho Yoon, Karina E. Hew, Minsoon Kim, Diana J. Azzam, Jun Sun, Dekuang Zhao, Tan A. Ince, Wenbin Liu, Wei Guo, Zhi Wei, Gao Zhang, Gordon Mills, Joyce M. Slingerland

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Abstract

Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition. Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts. Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1þ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting. Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials.

Original languageEnglish (US)
Pages (from-to)4874-4886
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number19
DOIs
StatePublished - Oct 1 2018
Externally publishedYes

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Neoplastic Stem Cells
Mitogen-Activated Protein Kinase Kinases
Ovarian Neoplasms
Stem Cells
Growth
Phosphotransferases
Neoplasms
Heterografts
Proteomics
Apoptosis
cdc Genes
Heterologous Transplantation
src-Family Kinases
Atlases
Autophagy
Therapeutics
Cell Cycle Checkpoints
Population
Cell Cycle
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Simpkins, F., Jang, K., Yoon, H., Hew, K. E., Kim, M., Azzam, D. J., ... Slingerland, J. M. (2018). Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells. Clinical Cancer Research, 24(19), 4874-4886. https://doi.org/10.1158/1078-0432.CCR-17-3697

Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells. / Simpkins, Fiona; Jang, Kibeom; Yoon, Hyunho; Hew, Karina E.; Kim, Minsoon; Azzam, Diana J.; Sun, Jun; Zhao, Dekuang; Ince, Tan A.; Liu, Wenbin; Guo, Wei; Wei, Zhi; Zhang, Gao; Mills, Gordon; Slingerland, Joyce M.

In: Clinical Cancer Research, Vol. 24, No. 19, 01.10.2018, p. 4874-4886.

Research output: Contribution to journalArticle

Simpkins, F, Jang, K, Yoon, H, Hew, KE, Kim, M, Azzam, DJ, Sun, J, Zhao, D, Ince, TA, Liu, W, Guo, W, Wei, Z, Zhang, G, Mills, G & Slingerland, JM 2018, 'Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells', Clinical Cancer Research, vol. 24, no. 19, pp. 4874-4886. https://doi.org/10.1158/1078-0432.CCR-17-3697
Simpkins, Fiona ; Jang, Kibeom ; Yoon, Hyunho ; Hew, Karina E. ; Kim, Minsoon ; Azzam, Diana J. ; Sun, Jun ; Zhao, Dekuang ; Ince, Tan A. ; Liu, Wenbin ; Guo, Wei ; Wei, Zhi ; Zhang, Gao ; Mills, Gordon ; Slingerland, Joyce M. / Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 19. pp. 4874-4886.
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T1 - Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells

AU - Simpkins, Fiona

AU - Jang, Kibeom

AU - Yoon, Hyunho

AU - Hew, Karina E.

AU - Kim, Minsoon

AU - Azzam, Diana J.

AU - Sun, Jun

AU - Zhao, Dekuang

AU - Ince, Tan A.

AU - Liu, Wenbin

AU - Guo, Wei

AU - Wei, Zhi

AU - Zhang, Gao

AU - Mills, Gordon

AU - Slingerland, Joyce M.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition. Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts. Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1þ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting. Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials.

AB - Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition. Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts. Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1þ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting. Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials.

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