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A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments will help inform treatment regimes. The nonreceptor tyrosine kinase SRC regulates many cellular signalling processes, and pharmacological inhibition has long been a target of cancer drug discovery projects. Here, we describe the in vitro and in vivo characterisation of the small‐molecule SRC inhibitor AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine‐419 of SRC (IC50 ~ 100 nm) in many cancer cell lines; however, inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a subset of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using reverse‐phase protein array (RPPA) analysis. We demonstrate that SRC is activated in response to treatment of KRAS‐mutant colorectal cell lines with MEK inhibitors (trametinib or AZD6244) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 had reduced EGFR, FAK and SRC compensatory activation, and cell viability was synergistically inhibited. In vivo, trametinib treatment of mice‐bearing HCT116 tumours increased phosphorylation of SRC on Tyr419, and, when combined with AZD0424, inhibition of tumour growth was greater than with trametinib alone. We also demonstrate that drug‐induced resistance to trametinib is not re‐sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however, inhibition of SRC remains an effective way to block invasion of trametinib‐resistant tumour cells. These data imply that SRC inhibition may offer a useful addition to MEK inhibitor combination strategies. [ABSTRACT FROM AUTHOR]

Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti‐HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib‐resistant breast cancer cell line (SKBR‐3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor‐1 (PAI‐1) was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C‐C motif) ligand 5 (CCL5). Functional assays showed that PAI‐1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI‐1 and CCL5 decreased cell proliferation and migration in saracatinib‐resistant cells. We also showed that targeting PAI‐1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings. [ABSTRACT FROM AUTHOR]

Background: SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. Aim: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. Materials and Methods: The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining. Results: Bosu induced the massive caspase-independent cell death, and blocked autophagy flux, which resulted from lysosomal dysfunction. Lysosomal dysfunction caused by Bosu was due to lysosomal membrane permeabilization (LMP), which resulted in the release of lysosomal hydrolases including cathepsin B. Conclusion: Our data suggest that Bosu induces the cell death through induction of LMP in melanoma cells and is a promising therapeutic agent for treatment of melanoma in both dogs and humans. [ABSTRACT FROM AUTHOR]

A theoretical study on binding orientations and quantitative structure-activity relationship (QSAR) of a novel series of alkene-3-quinolinecarbonitriles acting as Src inhibitors has been carried out by using the docking study and three-dimensional QSAR (3D-QSAR) analyses. The appropriate binding orientations and conformations of these compounds interacting with Src kinase were revealed by the docking studies, and the established 3D-QSAR models show significant statistical quality and satisfactory predictive ability, with high R2 values and q2 values: comparative molecular field analysis (CoMFA) model ( q2 = 0.748, R2 = 0.972), comparative molecular similarity indices analysis (CoMSIA) model ( q2 = 0.731, R2 = 0.987). The systemic external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with $ R{^2}_{\!\!\!\rm pred} $ values of 0.818 and 0.892, $ {r^2}_{\!\!\!\rm m} $ values of 0.879 and 0.886, $ {r^2}_{\!\!\!\rm m(LOO)} $ values of 0.874 and 0.874, $ r^2_{\rm m(overall)} $ values of 0.879 and 0.885, respectively. Several key structural features of the compounds responsible for inhibitory activity were discussed in detail. Based on these structural factors, eight new compounds with quite higher predicted Src-inhibitory activities have been designed and presented. We hope these theoretical results can offer some valuable references for the pharmaceutical molecular design as well as the action mechanism analysis. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]