6 research outputs found
Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model
<div><p>Background</p><p>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 <i>in vitro</i> and <i>in vivo</i> preclinical colorectal (CRC) models.</p><p>Methods</p><p>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 IC<sub>50</sub> ≤ 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 <i>in vivo</i> efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive.</p><p>Results</p><p>We found that 8 out of 50 CRC cell lines reached an IC<sub>50</sub> ≤ 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.</p><p>Conclusion</p><p>Dasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines <i>in vitro</i>, 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.</p></div
Additional file 1: Table S1. of Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer
IC50 values and SEM for fifty-five colorectal cancer cell lines treated with TAK-960 as assessed by CyQuant proliferation assay. (TIFF 689 kb
Evaluation of baseline pathway gene expression between sensitive and resistant CRC cell lines.
<p>A) Pathway analysis of sensitive and resistant gene expression and KEGG pathway diagram shows that adherens junction is a pathway enriched in sensitive CRC cell lines (red shows the genes that are increased in the sensitive cell lines and include Src and FAK. B) Src and C) FAK gene expression are significantly elevated in sensitive when compared to resistant CRC cell lines.</p
Pharmacodynamic effects of dasatinib on the Src pathway.
<p>A) Treatment with dasatinib (0.8 μmol/L) at 0.5h, 1h, 2h, 4h, and 8h significantly reduced the activation of Src, FAK and paxillin at all time points examined in the HCT116 sensitive CRC cell line when compared to control. B) A decrease in Src activity was seen in 1 out of 3 CRC explants treated with dasatinib in the sensitive (CRC036) and resistant CRC explant (CRC027) measured at end of study (day 28). However, in both cases FAK activity appeared to be increased.</p
The effects of dasatinib on CRC cell lines <i>in vitro</i>.
<p>Fifty CRC cell lines were treated with dasatinib (dose 0.08–5 μmol/L) and proliferation was determined by an SRB assay. An IC<sub>50</sub> ≤ 0.08 μM were deemed sensitive to dasatinib. The CRC cell lines KM20, LS174T, SNU-977, WiDR, HCT-116, SW1417, SNU-796, and SKCO1 demonstrated sensitivity to dasatinib.</p