Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models

M. Pia Morelli, John J. Tentler, Gillian N. Kulikowski, Aik-Choon Tan, Erica L. Bradshaw-Pierce, Todd M. Pitts, Amy M. Brown, Sujatha Nallapareddy, John J. Arcaroli, Natalie J. Serkova, Manuel Hidalgo, Fortunato Ciardiello, S. Gail Eckhardt

Research output: Contribution to journalArticle

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Abstract

Purpose: Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%, supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor. Experimental Design: Transcriptional profiling and gene set enrichment analysis (baseline and posttreatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts. Results: In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G 1, and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups. Conclusion: These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative activity against KRAS-mutant CRC cell lines in vitro. In vivo, the combination showed additive effects that were associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects.

Original languageEnglish
Pages (from-to)1051-1062
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number4
DOIs
Publication statusPublished - 2012 Feb 15
Externally publishedYes

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Colorectal Neoplasms
Cell Line
Histone Deacetylase Inhibitors
Glucose
Positron-Emission Tomography
Phospholipids
Growth
Apoptosis
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Cell Cycle Checkpoints
vorinostat
AZD 6244
Mitogen-Activated Protein Kinases
Heterografts
Vascular Endothelial Growth Factor A
Cell Movement
Protons
Flow Cytometry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Morelli, M. P., Tentler, J. J., Kulikowski, G. N., Tan, A-C., Bradshaw-Pierce, E. L., Pitts, T. M., ... Eckhardt, S. G. (2012). Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. Clinical Cancer Research, 18(4), 1051-1062. https://doi.org/10.1158/1078-0432.CCR-11-1507

Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. / Morelli, M. Pia; Tentler, John J.; Kulikowski, Gillian N.; Tan, Aik-Choon; Bradshaw-Pierce, Erica L.; Pitts, Todd M.; Brown, Amy M.; Nallapareddy, Sujatha; Arcaroli, John J.; Serkova, Natalie J.; Hidalgo, Manuel; Ciardiello, Fortunato; Eckhardt, S. Gail.

In: Clinical Cancer Research, Vol. 18, No. 4, 15.02.2012, p. 1051-1062.

Research output: Contribution to journalArticle

Morelli, MP, Tentler, JJ, Kulikowski, GN, Tan, A-C, Bradshaw-Pierce, EL, Pitts, TM, Brown, AM, Nallapareddy, S, Arcaroli, JJ, Serkova, NJ, Hidalgo, M, Ciardiello, F & Eckhardt, SG 2012, 'Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models', Clinical Cancer Research, vol. 18, no. 4, pp. 1051-1062. https://doi.org/10.1158/1078-0432.CCR-11-1507
Morelli, M. Pia ; Tentler, John J. ; Kulikowski, Gillian N. ; Tan, Aik-Choon ; Bradshaw-Pierce, Erica L. ; Pitts, Todd M. ; Brown, Amy M. ; Nallapareddy, Sujatha ; Arcaroli, John J. ; Serkova, Natalie J. ; Hidalgo, Manuel ; Ciardiello, Fortunato ; Eckhardt, S. Gail. / Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 4. pp. 1051-1062.
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AU - Kulikowski, Gillian N.

AU - Tan, Aik-Choon

AU - Bradshaw-Pierce, Erica L.

AU - Pitts, Todd M.

AU - Brown, Amy M.

AU - Nallapareddy, Sujatha

AU - Arcaroli, John J.

AU - Serkova, Natalie J.

AU - Hidalgo, Manuel

AU - Ciardiello, Fortunato

AU - Eckhardt, S. Gail

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N2 - Purpose: Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%, supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor. Experimental Design: Transcriptional profiling and gene set enrichment analysis (baseline and posttreatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts. Results: In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G 1, and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups. Conclusion: These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative activity against KRAS-mutant CRC cell lines in vitro. In vivo, the combination showed additive effects that were associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects.

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