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

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

Research output: Contribution to journalArticle

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Article numbere0187173
JournalPLoS One
Volume12
Issue number11
DOIs
Publication statusPublished - 2017 Nov 1
Externally publishedYes

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colorectal neoplasms
Colorectal Neoplasms
explants
animal models
Cells
cell lines
Cell Line
neoplasms
Tumors
inhibitory concentration 50
Neoplasms
lissamine rhodamine B
Inhibitory Concentration 50
growth retardation
drug therapy
src Genes
neoplasm cells
Dasatinib
G1 Phase Cell Cycle Checkpoints
Chemotherapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Scott, A. J., Song, E. K., Bagby, S., Purkey, A., McCarter, M., Gajdos, C., ... Messersmith, W. A. (2017). Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model. PLoS One, 12(11), [e0187173]. https://doi.org/10.1371/journal.pone.0187173

Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model. / Scott, Aaron J.; Song, Eun Kee; Bagby, Stacey; Purkey, Alicia; McCarter, Martin; Gajdos, Csaba; Quackenbush, Kevin S.; Cross, Benjamin; Pitts, Todd M.; Tan, Aik-Choon; Eckhardt, S. Gail; Fenton, Hubert; Arcaroli, John; Messersmith, Wells A.

In: PLoS One, Vol. 12, No. 11, e0187173, 01.11.2017.

Research output: Contribution to journalArticle

Scott, AJ, Song, EK, Bagby, S, Purkey, A, McCarter, M, Gajdos, C, Quackenbush, KS, Cross, B, Pitts, TM, Tan, A-C, Eckhardt, SG, Fenton, H, Arcaroli, J & Messersmith, WA 2017, 'Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model', PLoS One, vol. 12, no. 11, e0187173. https://doi.org/10.1371/journal.pone.0187173
Scott, Aaron J. ; Song, Eun Kee ; Bagby, Stacey ; Purkey, Alicia ; McCarter, Martin ; Gajdos, Csaba ; Quackenbush, Kevin S. ; Cross, Benjamin ; Pitts, Todd M. ; Tan, Aik-Choon ; Eckhardt, S. Gail ; Fenton, Hubert ; Arcaroli, John ; Messersmith, Wells A. / Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model. In: PLoS One. 2017 ; Vol. 12, No. 11.
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abstract = "Background: 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. Methods: 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. Results: 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. Conclusion: 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.",
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AU - Scott, Aaron J.

AU - Song, Eun Kee

AU - Bagby, Stacey

AU - Purkey, Alicia

AU - McCarter, Martin

AU - Gajdos, Csaba

AU - Quackenbush, Kevin S.

AU - Cross, Benjamin

AU - Pitts, Todd M.

AU - Tan, Aik-Choon

AU - Eckhardt, S. Gail

AU - Fenton, Hubert

AU - Arcaroli, John

AU - Messersmith, Wells A.

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N2 - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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