Overcoming resistance to DNA damaging chemo- and radiotherapy – endothelial cell FAK is the key

A familiar target offers new promise in overcoming resistance to cancer chemotherapy and radiotherapy

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DNA damaging chemotherapy and radiotherapy still form the cornerstone of clinical cancer treatment strategies, despite more than two decades of intensive research into a variety of cancer cell targeted approaches. Unfortunately DNA damaging approaches to cancer treatment are notoriously associated with initial response, followed by the onset of treatment resistance. A new target reported in Nature by Tavora et al. describes a new endothelial cell target underpinning chemoresistance, and a potential new avenue for future therapy, that may help to reverse this familiar story of clinical response followed by onset of drug resistance.[1]

The cellular target in question is a rather familiar player in the cancer field known as focal adhesion kinase (FAK). FAK is an intracellular kinase that is already the subject of major cancer drug discovery efforts, due to its role in processes such as cell migration and invasion, and modulation of cell-cell junction integrity within the cancer cell.[2] The link between FAK and cancer stem cell survival and proliferation provides significant potential added value to the development of FAK inhibitors.[3]

The recent Nature study demonstrated that targeting endothelial-cell FAK in established tumours in genetically-engineered mouse models was sufficient to sensitize tumour cells to DNA-damaging therapies, with no apparent effect on blood vessel function per se. The use of sophisticated mouse models bearing cancer cell lines with specific endothelial-cell FAK deletion was crucial to test the study hypothesis. Furthermore, mechanistic studies show that endothelial-cell FAK is required for DNA damage-induced NF-kB activation and cytokine production, both of which are reduced on endothelial-cell FAK deletion. Finally, clinical relevance of these findings is presented in the case of lymphoma patients, where resistance to DNA damaging chemotherapy (doxorubicin) is commonly encountered in patients. Sections of human lymphoma samples taken at both diagnosis and relapse indicate substantial correlation between chemoresistance and endothelial-cell FAK levels in this disease setting.

To all cancer medicinal chemists out there, this powerful new target validation data on a clinically relevant and druggable target (at least within the cancer cell), should inspire further developments for future patient benefit.

[1] Tavora et al. Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature 2014; 514: 112-116.

[2] Lazaro et al. Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response. Endocrine-Related Cancer 2013; 20: 691-704.

[3] www.verastem.com/products/ (Accessed 10th February 2015)

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Andrew Westwell

Dr., Cardiff University

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