Dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer

Todd M. Pitts, Timothy P. Newton, Erica L. Bradshaw-Pierce, Rebecca Addison, John J. Arcaroli, Peter J. Klauck, Stacey M. Bagby, Stephanie L. Hyatt, Alicia Purkey, John J. Tentler, Aik-Choon Tan, Wells A. Messersmith, S. Gail Eckhardt, Stephen Leong

Research output: Contribution to journalArticle

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Abstract

Background: The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).

Materials and Methods: The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models.

Results: The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status.

Conclusions: The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.

Original languageEnglish
Article numbere113037
JournalPLoS One
Volume9
Issue number11
DOIs
Publication statusPublished - 2014 Nov 17
Externally publishedYes

Fingerprint

colorectal neoplasms
Colorectal Neoplasms
phosphotransferases (kinases)
Phosphotransferases
Pharmacology
phosphatidylinositol 3-kinase
Tumors
Phosphatidylinositol 3-Kinases
Heterografts
Cells
cell lines
neoplasms
Cell Line
Mitogen-Activated Protein Kinase Kinases
Neoplasms
immunoblotting
mitogen-activated protein kinase
Immunoblotting
Inhibitory Concentration 50
inhibitory concentration 50

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pitts, T. M., Newton, T. P., Bradshaw-Pierce, E. L., Addison, R., Arcaroli, J. J., Klauck, P. J., ... Leong, S. (2014). Dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer. PLoS One, 9(11), [e113037]. https://doi.org/10.1371/journal.pone.0113037

Dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer. / Pitts, Todd M.; Newton, Timothy P.; Bradshaw-Pierce, Erica L.; Addison, Rebecca; Arcaroli, John J.; Klauck, Peter J.; Bagby, Stacey M.; Hyatt, Stephanie L.; Purkey, Alicia; Tentler, John J.; Tan, Aik-Choon; Messersmith, Wells A.; Eckhardt, S. Gail; Leong, Stephen.

In: PLoS One, Vol. 9, No. 11, e113037, 17.11.2014.

Research output: Contribution to journalArticle

Pitts, TM, Newton, TP, Bradshaw-Pierce, EL, Addison, R, Arcaroli, JJ, Klauck, PJ, Bagby, SM, Hyatt, SL, Purkey, A, Tentler, JJ, Tan, A-C, Messersmith, WA, Eckhardt, SG & Leong, S 2014, 'Dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer', PLoS One, vol. 9, no. 11, e113037. https://doi.org/10.1371/journal.pone.0113037
Pitts TM, Newton TP, Bradshaw-Pierce EL, Addison R, Arcaroli JJ, Klauck PJ et al. Dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer. PLoS One. 2014 Nov 17;9(11). e113037. https://doi.org/10.1371/journal.pone.0113037
Pitts, Todd M. ; Newton, Timothy P. ; Bradshaw-Pierce, Erica L. ; Addison, Rebecca ; Arcaroli, John J. ; Klauck, Peter J. ; Bagby, Stacey M. ; Hyatt, Stephanie L. ; Purkey, Alicia ; Tentler, John J. ; Tan, Aik-Choon ; Messersmith, Wells A. ; Eckhardt, S. Gail ; Leong, Stephen. / Dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer. In: PLoS One. 2014 ; Vol. 9, No. 11.
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AU - Pitts, Todd M.

AU - Newton, Timothy P.

AU - Bradshaw-Pierce, Erica L.

AU - Addison, Rebecca

AU - Arcaroli, John J.

AU - Klauck, Peter J.

AU - Bagby, Stacey M.

AU - Hyatt, Stephanie L.

AU - Purkey, Alicia

AU - Tentler, John J.

AU - Tan, Aik-Choon

AU - Messersmith, Wells A.

AU - Eckhardt, S. Gail

AU - Leong, Stephen

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Y1 - 2014/11/17

N2 - Background: The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).Materials and Methods: The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models.Results: The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status.Conclusions: The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.

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