Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.

Dysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor acti...

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Main Authors: Aaron J Scott, Eun-Kee Song, Stacey Bagby, Alicia Purkey, Martin McCarter, Csaba Gajdos, Kevin S Quackenbush, Benjamin Cross, Todd M Pitts, Aik Choon Tan, S Gail Eckhardt, Hubert Fenton, John Arcaroli, Wells A Messersmith
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2017-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC5665512?pdf=render
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spelling doaj-ffa9c06bfd5b415295825fb53b2a273e2020-11-25T00:12:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011211e018717310.1371/journal.pone.0187173Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.Aaron J ScottEun-Kee SongStacey BagbyAlicia PurkeyMartin McCarterCsaba GajdosKevin S QuackenbushBenjamin CrossTodd M PittsAik Choon TanS Gail EckhardtHubert FentonJohn ArcaroliWells A MessersmithDysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models.CRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib. We treated 50 CRC cell lines with dasatinib for 72 hours and proliferation was assayed by a sulforhodamine B (SRB) assay; an IC50 ≤ 0.08 μmol/L was considered sensitive. We treated 17 patient-derived CRC explants with dasatinib (50 mg/kg/day, administered once-daily) for 28 days to determine in vivo efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive.We found that 8 out of 50 CRC cell lines reached an IC50 ≤ 0.08 μmol/L with dasatinib treatment. In addition, of 17 CRC explants grown in the xenograft mouse model, 2 showed sensitivity to dasatinib. The anti-tumor effects observed in this study were a result of G1 cell cycle arrest as the dasatinib sensitive CRC cell lines exhibited G1 inhibition. Moreover, those CRC cell lines that were responsive (0.08 μmol/L) to treatment demonstrated a significant baseline increase in Src and FAK gene expression.Dasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines in vitro, especially in those with increased Src expression at baseline, but only showed modest efficacy in CRC explants. Dasatinib is currently being studied in combination with chemotherapy in patients with advanced CRC, as its use as a single agent appears limited.http://europepmc.org/articles/PMC5665512?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Aaron J Scott
Eun-Kee Song
Stacey Bagby
Alicia Purkey
Martin McCarter
Csaba Gajdos
Kevin S Quackenbush
Benjamin Cross
Todd M Pitts
Aik Choon Tan
S Gail Eckhardt
Hubert Fenton
John Arcaroli
Wells A Messersmith
spellingShingle Aaron J Scott
Eun-Kee Song
Stacey Bagby
Alicia Purkey
Martin McCarter
Csaba Gajdos
Kevin S Quackenbush
Benjamin Cross
Todd M Pitts
Aik Choon Tan
S Gail Eckhardt
Hubert Fenton
John Arcaroli
Wells A Messersmith
Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.
PLoS ONE
author_facet Aaron J Scott
Eun-Kee Song
Stacey Bagby
Alicia Purkey
Martin McCarter
Csaba Gajdos
Kevin S Quackenbush
Benjamin Cross
Todd M Pitts
Aik Choon Tan
S Gail Eckhardt
Hubert Fenton
John Arcaroli
Wells A Messersmith
author_sort Aaron J Scott
title Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.
title_short Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.
title_full Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.
title_fullStr Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.
title_full_unstemmed Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.
title_sort evaluation of the efficacy of dasatinib, a src/abl inhibitor, in colorectal cancer cell lines and explant mouse model.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2017-01-01
description Dysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models.CRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib. We treated 50 CRC cell lines with dasatinib for 72 hours and proliferation was assayed by a sulforhodamine B (SRB) assay; an IC50 ≤ 0.08 μmol/L was considered sensitive. We treated 17 patient-derived CRC explants with dasatinib (50 mg/kg/day, administered once-daily) for 28 days to determine in vivo efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive.We found that 8 out of 50 CRC cell lines reached an IC50 ≤ 0.08 μmol/L with dasatinib treatment. In addition, of 17 CRC explants grown in the xenograft mouse model, 2 showed sensitivity to dasatinib. The anti-tumor effects observed in this study were a result of G1 cell cycle arrest as the dasatinib sensitive CRC cell lines exhibited G1 inhibition. Moreover, those CRC cell lines that were responsive (0.08 μmol/L) to treatment demonstrated a significant baseline increase in Src and FAK gene expression.Dasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines in vitro, especially in those with increased Src expression at baseline, but only showed modest efficacy in CRC explants. Dasatinib is currently being studied in combination with chemotherapy in patients with advanced CRC, as its use as a single agent appears limited.
url http://europepmc.org/articles/PMC5665512?pdf=render
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