Tumor P-glycoprotein correlates with efficacy of PF-3758309 in in vitro and in vivo models of colorectal cancer

Erica Lynn Bradshaw-Pierce, Todd M. Pitts, Aik-Choon Tan, Kelly McPhillips, Mark West, Daniel L. Gustafson, Charles Halsey, Leslie Nguyen, Nathan V. Lee, Julie L C Kan, Brion William Murray, S. Gail Eckhardt

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Abstract

P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1 (P-gp) expression was evaluated by microarray for these cell lines. P-gp expression was determined by western blot and activity determined by rhodamine efflux assay. Knock down of P-gp and pharmacologic inhibition of P-gp to restore PF-309 activity was performed in vitro. PF-309 activity was evaluated in vivo in cell line xenograft models and in primary patient derived tumor xenografts (PDTX). Mice were treated with 25 mg/kg PF-309 orally, twice daily. On the last day of treatment, tumor and plasma were collected for PF-309 analysis. Here we show that ABCB1 gene expression correlates with resistance to PF-309 treatment in vitro and the expression and activity of P-gp was verified in a panel of resistant cells. Furthermore, inhibition of P-gp increased the sensitivity of resistant cells, resulting in a 4-100-fold decrease in the IC50s. Eleven cell line xenografts and 12 PDTX models were treated with PF-309. From the cell line xenografts, we found a significant correlation between ABCB1 gene expression profiles and tumor response. We evaluated tumor and plasma concentrations for eight tumor models (three cell line xenografts and five PDTX models) and a significant correlation was found between tumor concentration and response. Additionally, we show that tumor concentration is approximately fourfold lower in tumors that express P-gp, verified by western blot. Our in vitro and in vivo data strongly suggests that PF-309 efficacy is influenced by the expression of tumor P-gp.

Original languageEnglish
Article numberArticle 22
JournalFrontiers in Pharmacology
Volume4 MAR
DOIs
Publication statusPublished - 2013 Aug 20
Externally publishedYes

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Keywords

  • Colorectal cancer
  • Intrinsic resistance
  • Mouse xenografts
  • P-glycoprotein
  • Pf-3758309

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Bradshaw-Pierce, E. L., Pitts, T. M., Tan, A-C., McPhillips, K., West, M., Gustafson, D. L., Halsey, C., Nguyen, L., Lee, N. V., Kan, J. L. C., Murray, B. W., & Eckhardt, S. G. (2013). Tumor P-glycoprotein correlates with efficacy of PF-3758309 in in vitro and in vivo models of colorectal cancer. Frontiers in Pharmacology, 4 MAR, [Article 22]. https://doi.org/10.3389/fphar.2013.00022