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


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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    • "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). "
    Aging Cell 03/2015; · 5.71 Impact Factor
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    • "The main accomplishment of our study was to observe that anti - SRC therapy may counteract anti - EGFR therapies based on cetuximab in some cell types , an interesting observation because a number of clinical trials are currently exploring this combination or the association of dasatinib with other therapies ( Montero et al , 2011 ) . "
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    ABSTRACT: Background: Cetuximab is often combined with radiotherapy in advanced SCCHN. Alternative routes bypassing inhibition of EGFR with cetuximab may overshadow the efficacy of this combination. We undertook this study to investigate a possible role of dasatinib in this scenario. Methods: The SCC5, SCC25, SCC29, FaDu and A431 cell lines were assessed in vitro for cell proliferation under cetuximab and dasatinib treatments. In FaDu and A431 cells, dasatinib plus cetuximab resulted in higher proliferation than cetuximab alone. Then, FaDu and A431 cells were implanted into subcutaneous tissue of athymic mice that were irradiated with 30 Gy in 10 fractions over 2 weeks, and treated with cetuximab and dasatinib. Tumour growth, DNA synthesis and angiogenesis were determined. The EGFR, RAS-GTP activity, phosphorylated AKT, ERK1/2, SRC protein levels and VEGF secretion were determined in vitro. Results: The addition of dasatinib to cetuximab and radiotherapy increased tumour growth, DNA synthesis and angiogenesis that were associated with RAS, AKT and ERK1/2 activation, and SRC inhibition in FaDu and A431 cells. Conclusions: In xenografts derived from these two cell lines, dasatinib did not improve the efficacy of cetuximab combined with radiotherapy. On the contrary, it worsened tumour control achieved by the combination of these two treatments.
    British Journal of Cancer 07/2014; DOI:10.1038/bjc.2014.432 · 4.84 Impact Factor
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    • "We revealed that PDGFR- beta was undetectable in non treated parental cells and non-irradiated lung sphere cells; however it was highly expressed in radiation survived sphere cells and adherent radiation survived cells. PDFGR- beta is a receptor tyrosine kinase (RTK) whose downstream signaling is effectively abrogated by second generation RTK inhibitors, such as Axitinib (AG-013736) [74] and dasatinib [75,76]. Using a classical clonogenic assay for testing the effect of ionizing radiation, axitinib, dasatinib and the combination of IR with axitinib or dasatinib treatment, we observed that RDGFR signaling may be important for NSCLC radiation resistance as the combination of IR with dasatinib or axitinib treatment significantly increases the efficacy of IR treatment in NSCLC cells. "
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    ABSTRACT: Ionizing radiation (IR) is used for patients diagnosed with unresectable non small cell lung cancer (NSCLC), however radiotherapy remains largely palliative due to radioresistance. Cancer stem cells (CSCs), as well as epithelial-mesenchymal transition (EMT), may contribute to drug and radiation resistance mechanisms in solid tumors. Here we investigated the molecular phenotype of A549 and H460 NSCLC cells that survived treatment with IR (5Gy) and are growing as floating tumor spheres and cells that are maintained in a monolayer after irradiation. Non-irradiated and irradiated cells were collected after one week, seeded onto ultra low attachment plates and propagated as tumor spheres. Bulk NSCLC cells which survived radiation and grew in spheres express cancer stem cell surface and embryonic stem cell markers and are able to self-renew, and generate differentiated progeny. These cells also have a mesenchymal phenotype. Particularly, the radiation survived sphere cells express significantly higher levels of CSC markers (CD24 and CD44), nuclear β-catenin and EMT markers (Snail1, Vimentin, and N-cadherin) than non-irradiated lung tumor sphere cells. Upregulated levels of Oct-4, Sox2 and beta-catenin were detected in H460 cells maintained in a monolayer after irradiation, but not in radiation survived adherent A459 cells. PDGFR-beta was upregulated in radiation survived sphere cells and in radiation survived adherent cells in both A549 and H460 cell lines. Combining IR treatment with axitinib or dasatinib, inhibitors with anti-PDFGR activity, potentiates the efficacy of NSCLC radiotherapy in vitro. Our findings suggest that radiation survived cells have a complex phenotype combining the properties of CSCs and EMT. CD44, SNAIL and PDGFR-beta are dramatically upregulated in radiation survived cells and might be considered as markers of radiotherapy response in NSCLC.
    Molecular Cancer 08/2013; 12(1):94. DOI:10.1186/1476-4598-12-94 · 4.26 Impact Factor
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