title: Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models.
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.
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.forename: Gillian N
authors.initials: GN
authors.lastname: Kulikowski
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.forename: Heather M
authors.initials: HM
authors.lastname: Selby
authors.forename: Maria I
authors.initials: MI
authors.lastname: Kachaeva
authors.forename: Kelly L
authors.initials: KL
authors.lastname: McPhillips
authors.forename: Blair C
authors.initials: BC
authors.lastname: Britt
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
keywords: EMT; PAK; PF-3758309; colorectal cancer; intrinsic resistance
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