Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth

ABSTRACT: A common limitation of cancer treatments is chemotherapy resistance. We have previously identified a molecular mechanism where chemotherapy resistance is regulated by endothelial cells. Endothelial cell specific knockout of focal adhesion kinase (FAK) sensitises tumour cells to DNA-damaging therapies, reducing tumour growth in mice. Our current study addresses the kinase dependent component 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 specific inactivation of the FAK kinase domain in endothelial cells of blood vessels in established subcutaneous B16F0 tumours sensitises melanoma cells to doxorubicin. Tumour growth was reduced in response to doxorubicin treatment in FAK kinase-dead but not in wild-type mice. Furthermore, we demonstrate that doxorubicin reduces perivascular proliferation, enhances apoptosis and DNA-damage in endothelial cell FAK kinase dead tumours. When we treated human pulmonary microvascular endothelial cells with the FAK kinase inhibitors defactinib, PF-562,271 and PF-573,228 in combination with doxorubicin, we observed a reduction in cytokine levels, implying a possible mechanism for FAK kinase domain in chemosensitisation. Together, these results confirm the role of the kinase domain of EC-FAK in chemosensitising tumour cells to doxorubicin.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Endothelial Cell

DISEASE(S): Disease Free

SUBMITTER: Pedro Casado-Izquierdo  

LAB HEAD: Pedro R. Cutillas

PROVIDER: PXD019728 | Pride | 2021-11-02

REPOSITORIES: Pride