Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models
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 CRC cell lines to identify potential bi...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2013-03-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2013.00035/full |
| _version_ | 1811324543965331456 |
|---|---|
| author | Todd M Pitts Gillian N Kulikowski Aik-Choon eTan Brion William Murray John J Arcaroli John J Tentler Anna eSpreafico Heather M Selby Maria I Kachaeva Kelly L McPhillips Blair C Britt Erica Lynn Bradshaw-Pierce Erica Lynn Bradshaw-Pierce Wells A Messersmith Marileila eVarella-Garcia S. Gail eEckhardt |
| author_facet | Todd M Pitts Gillian N Kulikowski Aik-Choon eTan Brion William Murray John J Arcaroli John J Tentler Anna eSpreafico Heather M Selby Maria I Kachaeva Kelly L McPhillips Blair C Britt Erica Lynn Bradshaw-Pierce Erica Lynn Bradshaw-Pierce Wells A Messersmith Marileila eVarella-Garcia S. Gail eEckhardt |
| author_sort | Todd M Pitts |
| collection | DOAJ |
| description | 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 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 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. |
| first_indexed | 2024-04-13T14:16:15Z |
| format | Article |
| id | doaj.art-45117471fa79483fb8bbd3e8ebc48543 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T14:16:15Z |
| publishDate | 2013-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-45117471fa79483fb8bbd3e8ebc485432022-12-22T02:43:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122013-03-01410.3389/fphar.2013.0003543261Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer ModelsTodd M Pitts0Gillian N Kulikowski1Aik-Choon eTan2Brion William Murray3John J Arcaroli4John J Tentler5Anna eSpreafico6Heather M Selby7Maria I Kachaeva8Kelly L McPhillips9Blair C Britt10Erica Lynn Bradshaw-Pierce11Erica Lynn Bradshaw-Pierce12Wells A Messersmith13Marileila eVarella-Garcia14S. Gail eEckhardt15University of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverPfizer Global Research and DevelopmentUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverPfizer Global Research and DevelopmentUniversity of Colorado DenverUniversity of Colorado DenverUniversity of Colorado DenverThe 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 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 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.http://journal.frontiersin.org/Journal/10.3389/fphar.2013.00035/fullcolorectal cancerEMTPF-3758309intrinsic resistancePAK |
| spellingShingle | Todd M Pitts Gillian N Kulikowski Aik-Choon eTan Brion William Murray John J Arcaroli John J Tentler Anna eSpreafico Heather M Selby Maria I Kachaeva Kelly L McPhillips Blair C Britt Erica Lynn Bradshaw-Pierce Erica Lynn Bradshaw-Pierce Wells A Messersmith Marileila eVarella-Garcia S. Gail eEckhardt Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models Frontiers in Pharmacology colorectal cancer EMT PF-3758309 intrinsic resistance PAK |
| title | Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models |
| title_full | Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models |
| title_fullStr | Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models |
| title_full_unstemmed | Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models |
| title_short | Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models |
| title_sort | association of the epithelial to mesenchymal transition emt phenotype with responsiveness to the p21 activated kinase inhibitor pf 3758309 in colon cancer models |
| topic | colorectal cancer EMT PF-3758309 intrinsic resistance PAK |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2013.00035/full |
| work_keys_str_mv | AT toddmpitts associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT gilliannkulikowski associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT aikchoonetan associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT brionwilliammurray associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT johnjarcaroli associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT johnjtentler associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT annaespreafico associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT heathermselby associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT mariaikachaeva associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT kellylmcphillips associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT blaircbritt associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT ericalynnbradshawpierce associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT ericalynnbradshawpierce associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT wellsamessersmith associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT marileilaevarellagarcia associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels AT sgaileeckhardt associationoftheepithelialtomesenchymaltransitionemtphenotypewithresponsivenesstothep21activatedkinaseinhibitorpf3758309incoloncancermodels |