A common limitation of cancer treatments is chemotherapy resistance. We have identified previously that endothelial cell specific deletion of focal adhesion kinase (FAK) sensitises tumour cells to DNA-damaging therapies, reducing tumour growth in mice. Our current study addresses the kinase activity dependency of endothelial-cell FAK sensitisation to the DNA damaging chemotherapeutic drug doxorubicin. FAK is recognised as a therapeutic target in tumour cells, leading to the development of a range of inhibitors, the majority being ATP competitive kinase inhibitors. We demonstrate that inactivation of endothelial-cell FAK kinase domain (kinase dead) (EC-FAK kinase-dead) in established subcutaneous B16F0 tumours, improves melanoma cells sensitisation to doxorubicin. Doxorubicin treatment in EC-FAK kinase-dead mice reduced the percentage change in exponential B16F0 tumour growth further than in wild-type mice. There was no effect on tumour blood vessel numbers, vessel perfusion or doxorubicin delivery between genotypes, suggesting a possible angiocrine effect on the regulation of tumour growth. Doxorubicin reduced perivascular malignant cell proliferation, whilst enhancing perivascular tumour cell apoptosis and DNA-damage in tumours grown in EC-FAK kinase dead mice 48 hrs after doxorubicin injection. Human pulmonary microvascular endothelial-cells treated with the pharmacological FAK kinase inhibitors defactinib, PF-562,271 or PF-573,228 in combination with doxorubicin, also reduced cytokine expression levels. Together, these data suggest that targeting EC-FAK kinase activity may alter angiocrine signals that correlate with improved acute tumour cell chemosensitisation.

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