Article

Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

Instituto de Biología Molecular y Celular del Cáncer-Centro de Investigación del Cáncer (CIC), Consejo Superior de Investigaciones Cientificas (CSIC)-Universidad de Salamanca, Salamanca, Spain.
Clinical Cancer Research (Impact Factor: 8.72). 06/2011; 17(17):5546-52. DOI: 10.1158/1078-0432.CCR-10-2616
Source: PubMed

ABSTRACT

Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale.

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    • "Dasatinib which was first designed as a potential immunosuppressive agent, inhibits both Src kinase and RTK of PDGF (Swords et al., 2009). It is used in cancer therapy and in the treatment of a certain type of chronic myeloid leukemia due to its anti-angiogenic and anti-proliferative properties (Johnson et al., 2005; Montero et al., 2011). The therapeutic inhibitory effect on Src kinase was shown in a model of BLM-induced PF in mice (Hu et al., 2014). "
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    ABSTRACT: Anti-fibrotic effect of dasatinib, a platelet-derived growth factor receptor (PDGFR) and Src-kinase inhibitor, was tested on pulmonary fibrosis (PF). Adult mice were divided into four groups: mice dissected 21 d after the bleomycin (BLM) instillation (0.08 mg/kg in 200 µl) (I) and their controls (II), and mice treated with dasatinib (8 mg/kg in 100 µl, gavage) for one week 14 d after BLM instillation and dissected 21 d after instillation (III) and their controls (IV). The fibrosis score and the levels of fibrotic markers were analyzed in lungs. BLM treatment-induced cell proliferation and increased the levels of collagen-1, alpha smooth muscle actin, phospho (p)-PDGFR-alpha, p-Src, p-extracellular signal-regulated kinases1/2 and p-cytoplasmic-Abelson-kinase (c-Abl) in lungs, and down-regulated PTEN expression. Dasatinib reversed these alterations in the fibrotic lung. Dasatinib limited myofibroblast activation and collagen-1 accumulation by the inhibition of PDGFR-alpha, and Src and c-Abl activations. In conclusion, dasatinib may be a novel tyrosine and Src-kinase inhibitor for PF regression in mice.
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    • "It is synthesised from a 2-aminothiazole which is considered the novel Src family kinase inhibitor template [13]. Dasatinib is indicated for the treatment of chronic, accelerated or blast-phase myeloid leukaemia , with resistance or intolerance to prior therapy [14] [15] [16] [17]. "
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    ABSTRACT: The electrochemical oxidation mechanism of the anticancer drug and kinases inhibitor dasatinib was studied by cyclic, differential pulse and square wave voltammetry using a glassy carbon electrode. Dasatinib undergoes irreversible, pH-dependent oxidation in a cascade mechanism. For electrolyte with pH < 9.0 two peaks corresponding to consecutive charge transfer reactions that involve the transfer of the same number of electrons and protons were observed. For electrolytes with pH > 9.0 only one oxidation peak was observed. The UV-Vis spectra of dasatinib were recorded as a function of pH. The thiazole moiety was identified as the electroactive centre through comparative studies with compounds with similar structures and an oxidation mechanism of dasatinib was proposed. The analytical determination of dasatinib was carried out by differential pulse voltammetry in buffer and serum samples. Adequate recovery results in spiked serum samples were obtained and the matrix effect, serum dilution and dasatinib concentration were evaluated.
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    • "Of 46 agents tested, dasatinib (D) and quercetin (Q) showed particular promise in clearing senescent cells. D is a multi-tyrosine kinase inhibitor used for treating cancers (Montero et al. 2011) that interferes with EFNB-mediated repression of apoptosis (Chang et al. 2008; Xi et al. 2012). D preferentially reduced viability and caused cell death in senescent human preadipocytes, but was much less effective on senescent HUVECs (Fig. 2A). "

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