Reference Detail

Ref Type Journal Article
PMID (22244830)
Authors Arai R, Tsuda M, Watanabe T, Ose T, Obuse C, Maenaka K, Minami A, Ohba Y
Title Simultaneous inhibition of Src and Aurora kinases by SU6656 induces therapeutic synergy in human synovial sarcoma growth, invasion and angiogenesis in vivo.
Journal European journal of cancer (Oxford, England : 1990)
Vol 48
Issue 15
Date 2012 Oct
URL
Abstract Text Synovial sarcoma is an obstinate, high-grade malignancy because of its modest responses to radiotherapy and chemotherapy; the identification of effective therapeutics for this sarcoma is therefore necessary. Inhibition of Src family kinases (SFKs) suppresses the proliferation of synovial sarcoma cells in vitro, as we have previously reported. In this study, to validate the efficacy of Src inhibition in vivo, we employed SU6656, which was originally identified as a specific SFK inhibitor. SU6656 treatment significantly impaired the growth of established, existing tumours formed by synovial sarcoma cells in mice. Tumour cell invasion into the surrounding tissues was also abolished by SU6656. It is noteworthy that SU6656 but not PP2 induced a defect in cleavage furrow formation during cytokinesis, resulting in G2/M accumulation and subsequent apoptosis. Intriguingly, SU6656 abrogated the catalytic activities of Aurora kinases and led to the down-regulation of phosphorylated histone H3 coincidently with p53 accumulation, as did the Aurora kinase inhibitor VX-680. Structural comparison indicated an extensive similarity between the catalytic domains of SFKs and Aurora kinases. The structural analysis also revealed the potential binding mode of SU6656 to the ATP-binding cleft of Aurora B via four hydrogen bonds. SU6656 prevented angiogenesis within the tumours by attenuating vascular endothelial growth factor (VEGF) production by tumour cells and the subsequent chemotaxis of endothelial cells; these effects were the result of the inhibition of SFKs but not Aurora kinases. Based on these results, we hereby report a novel property of SU6656 as a dual inhibitor of SFKs and Aurora kinases, the suppression of both of which effectively abrogates tumour development and the progression of synovial sarcoma in vivo.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
SU6656 SU6656 is a small molecule inhibitor of SRC, which may lead to inhibition of tumor growth and decreased tumor invasion and angiogenesis (PMID: 22244830).
Drug Name Trade Name Synonyms Drug Classes Drug Description
SU6656 SRC Inhibitor 26 SU6656 is a small molecule inhibitor of SRC, which may lead to inhibition of tumor growth and decreased tumor invasion and angiogenesis (PMID: 22244830).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown synovial sarcoma not applicable SU6656 Preclinical - Cell line xenograft Actionable In a preclinical study, SU6656 treatment decreased cell proliferation of synovial sarcoma cells in culture and inhibited tumor growth and blocked tumor invasion in cell line xenograft models (PMID: 22244830). 22244830