Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models

Todd M. Pitts, Gillian N. Kulikowski, Aik Choon Tan, Brion W. Murray, John J. Arcaroli, John J. Tentler, Anna Spreafico, Heather M. Selby, Maria I. Kachaeva, Kelly L. McPhillips, Blair C. Britt, Erica L. Bradshaw-Pierce, Wells A. Messersmith, Marileila Varella-Garcia, S. Gail Eckhardt

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Abstract

The p21-activated kinase (PAK) family of serine/threonine kinases, which are overexpressed in several cancer types, are critical mediators of cell survival, motility, mitosis, transcription, and translation. In the study presented here, we utilized a panel of colorectal cancer (CRC) cell lines to identify potential biomarkers of sensitivity or resistance that may be used to individualize therapy to the PAK inhibitor PF-03758309. We observed a wide range of proliferative responses in the CRC cell lines exposed to PF-03758309, this response was recapitulated in other phenotypic assays such as anchorage-independent growth, three-dimensional (3D) tumor spheroid formation, and migration. Interestingly, we observed that cells most sensitive to PF-03758309 exhibited up-regulation of genes associated with a mesenchymal phenotype (CALD1, VIM, ZEB1) and cells more resistant had an up-regulation of genes associated with an epithelial phenotype (CLDN2, CDH1, CLDN3, CDH17) allowing us to derive an epithelial-to-mesenchymal transition (EMT) gene signature for this agent. We assessed the functional role of EMT-associated genes in mediating responsiveness to PF-3758309, by targeting known genes and transcriptional regulators of EMT. We observed that suppression of genes associated with the mesenchymal phenotype conferred resistance to PF-3758309, in vitro and in vivo. These results indicate that PAK inhibition is associated with a unique response phenotype in CRC and that further studies should be conducted to facilitate both patient selection and rational combination strategies with these agents.

Original languageEnglish
Article numberArticle 35
JournalFrontiers in Pharmacology
Volume4 MAR
DOIs
Publication statusPublished - 2013 Aug 21

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Keywords

  • Colorectal cancer
  • Emt
  • Intrinsic resistance
  • PAK
  • Pf-3758309

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pitts, T. M., Kulikowski, G. N., Tan, A. C., Murray, B. W., Arcaroli, J. J., Tentler, J. J., Spreafico, A., Selby, H. M., Kachaeva, M. I., McPhillips, K. L., Britt, B. C., Bradshaw-Pierce, E. L., Messersmith, W. A., Varella-Garcia, M., & Eckhardt, S. G. (2013). Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models. Frontiers in Pharmacology, 4 MAR, [Article 35]. https://doi.org/10.3389/fphar.2013.00035