Rational combination of a MEK inhibitor, selumetinib, and the wnt/calcium pathway modulator, cyclosporin a, in preclinical models of colorectal cancer

Anna Spreafico, John J. Tentler, Todd M. Pitts, Aik-Choon Tan, Mark A. Gregory, John J. Arcaroli, Peter J. Klauck, Martine C. McManus, Ryan J. Hansen, Jihye Kim, Lindsey N. Micel, Heather M. Selby, Timothy P. Newton, Kelly L. McPhillips, Daniel L. Gustafson, James V. DeGregori, Wells A. Messersmith, Robert A. Winn, S. Gail Eckhardt

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Purpose: The mitogen-Activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-Agent activity in colorectal cancer, indicating that rational combination strategies are needed. Experimental Design: In this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca+ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer. Results: Importantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa+ inhibitors, which may explain the observed synergistic antitumor effects. Conclusions: These results strengthen the hypothesis that targeting both theMEKandWnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer.

Original languageEnglish
Pages (from-to)4149-4162
Number of pages14
JournalClinical Cancer Research
Volume19
Issue number15
DOIs
Publication statusPublished - 2013 Aug 1
Externally publishedYes

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Wnt Signaling Pathway
Mitogen-Activated Protein Kinase Kinases
Cyclosporine
Colorectal Neoplasms
Calcium
Apoptosis
Neoplasms
Mitogen-Activated Protein Kinases
Small Interfering RNA
AZD 6244
Cell Survival
Research Design
Cell Proliferation
Ligands
Cell Line
Therapeutics
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rational combination of a MEK inhibitor, selumetinib, and the wnt/calcium pathway modulator, cyclosporin a, in preclinical models of colorectal cancer. / Spreafico, Anna; Tentler, John J.; Pitts, Todd M.; Tan, Aik-Choon; Gregory, Mark A.; Arcaroli, John J.; Klauck, Peter J.; McManus, Martine C.; Hansen, Ryan J.; Kim, Jihye; Micel, Lindsey N.; Selby, Heather M.; Newton, Timothy P.; McPhillips, Kelly L.; Gustafson, Daniel L.; DeGregori, James V.; Messersmith, Wells A.; Winn, Robert A.; Eckhardt, S. Gail.

In: Clinical Cancer Research, Vol. 19, No. 15, 01.08.2013, p. 4149-4162.

Research output: Contribution to journalArticle

Spreafico, A, Tentler, JJ, Pitts, TM, Tan, A-C, Gregory, MA, Arcaroli, JJ, Klauck, PJ, McManus, MC, Hansen, RJ, Kim, J, Micel, LN, Selby, HM, Newton, TP, McPhillips, KL, Gustafson, DL, DeGregori, JV, Messersmith, WA, Winn, RA & Eckhardt, SG 2013, 'Rational combination of a MEK inhibitor, selumetinib, and the wnt/calcium pathway modulator, cyclosporin a, in preclinical models of colorectal cancer', Clinical Cancer Research, vol. 19, no. 15, pp. 4149-4162. https://doi.org/10.1158/1078-0432.CCR-12-3140
Spreafico, Anna ; Tentler, John J. ; Pitts, Todd M. ; Tan, Aik-Choon ; Gregory, Mark A. ; Arcaroli, John J. ; Klauck, Peter J. ; McManus, Martine C. ; Hansen, Ryan J. ; Kim, Jihye ; Micel, Lindsey N. ; Selby, Heather M. ; Newton, Timothy P. ; McPhillips, Kelly L. ; Gustafson, Daniel L. ; DeGregori, James V. ; Messersmith, Wells A. ; Winn, Robert A. ; Eckhardt, S. Gail. / Rational combination of a MEK inhibitor, selumetinib, and the wnt/calcium pathway modulator, cyclosporin a, in preclinical models of colorectal cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 15. pp. 4149-4162.
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T1 - Rational combination of a MEK inhibitor, selumetinib, and the wnt/calcium pathway modulator, cyclosporin a, in preclinical models of colorectal cancer

AU - Spreafico, Anna

AU - Tentler, John J.

AU - Pitts, Todd M.

AU - Tan, Aik-Choon

AU - Gregory, Mark A.

AU - Arcaroli, John J.

AU - Klauck, Peter J.

AU - McManus, Martine C.

AU - Hansen, Ryan J.

AU - Kim, Jihye

AU - Micel, Lindsey N.

AU - Selby, Heather M.

AU - Newton, Timothy P.

AU - McPhillips, Kelly L.

AU - Gustafson, Daniel L.

AU - DeGregori, James V.

AU - Messersmith, Wells A.

AU - Winn, Robert A.

AU - Eckhardt, S. Gail

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Purpose: The mitogen-Activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-Agent activity in colorectal cancer, indicating that rational combination strategies are needed. Experimental Design: In this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca+ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer. Results: Importantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa+ inhibitors, which may explain the observed synergistic antitumor effects. Conclusions: These results strengthen the hypothesis that targeting both theMEKandWnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer.

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