Abstract
BackgroundDysregulation 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.MethodsCRC 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.ResultsWe 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.ConclusionDasatinib 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.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies in Western countries, and the prognosis remains dismal in the metastatic setting [1]
We first investigated the antiproliferative effects of dasatinib on 50 CRC cell lines
Analysis of Src (Fig 5B) and focal adhesion kinase (FAK) (Fig 5C) gene expression by RNA Seq show that both Src and FAK are significantly upregulated at basline in sensitive versus resistant CRC cell lines. These results suggest that dasatinib has greater anti-proliferative activity in CRC cell lines that exhibit higher levels of Src and FAK gene expression
Summary
Colorectal cancer (CRC) is one of the most common malignancies in Western countries, and the prognosis remains dismal in the metastatic setting [1]. Aberrant Src activity has been shown to play a central role in tumorigenesis of all stages of CRC [3, 4]. The Src pathway is activated in approximately 80% of all human colon tumors, including adenomatous polyps, and this activation is an important factor in the induction and progression of tumors [5]. Src activation is an independent prognostic indicator at all stages of CRC, further demonstrating its vital role in sequential progression of pre-malignant tumors, to malignancy, and tumor metastasis [7]. 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
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