Src and focal adhesion kinase as therapeutic targets in cancer
Introduction
As our understanding of the complexities of cancer biology has increased, the ability to exploit unique features of tumour cells with molecularly targeted therapies has become a reality and has radically changed the treatment of cancer over the past 10 years. Many of these molecularly targeted agents are tyrosine kinase inhibitors with the most notable success being the use of Gleevec, which targets BCR–ABL, for the treatment of chronic myeloid leukaemia [1]. In this review we will focus on two non-receptor tyrosine kinases: Src and FAK. Src and FAK have multiple cellular functions and modulation of their activities can alter cell responses that are often perturbed in cancer such as survival, migration and invasion [2, 3, 4, 5]. Furthermore, many of their functions in cells are intimately linked, and they act to integrate signals from growth factor receptors and integrin heterodimers to initiate a number of downstream signals (Figure 1). Tyrosine kinase inhibitors directed against both Src and FAK have been developed, and a number of clinical trials are now underway to assess their potential use for the treatment of a wide range of solid tumours. Here we will review the rationale for their use and discuss future perspectives.
Section snippets
Src as a therapeutic target
Src is the prototypic member of a family of nine non-receptor tyrosine kinases and was the first identified proto-oncogene. Over the past 25 years increased Src expression and/or activity has been described in many different tumour types, but is best documented in the colon and breast [2, 5]. However, it has only been relatively recently that a serious interest in Src as a therapeutic target in cancer has evolved. This has been partly owing to the incomplete understanding of the role that Src
Proliferation
Early studies demonstrated a requirement for Src family kinases in growth factor driven proliferation of fibroblasts. However, in tumour cells the situation is much more complex and there is growing evidence from studies using both molecular and pharmacological interventions that many tumour cells are not dependent on Src activity for their proliferation [7, 8, 9••, 10]. In support of this, current available data from clinical trials of Src inhibitors as single agents have shown no objective
FAK as a therapeutic target
FAK is involved in a number of processes that can have impact on the malignant phenotype, the importance of which is not fully understood. In support however, of a direct role for FAK in tumorigenesis targeted deletion of fak in mouse skin, revealed an absolute requirement for FAK in malignant tumour formation [34•]. Numerous reports have reported FAK overexpression in various human epithelial tumour types [3, 35, 36]. In some cases this has been linked to poor clinical outcome while other
What next for Src and FAK inhibitors?
The current Phase I trials with both Src and FAK inhibitors have shown that they are fairly well tolerated as single agents, and the challenge now is how to take these agents forward. One major problem is how to assess which tumours will respond to Src or FAK inhibitors so that patients can be selected who will most probably benefit from treatment. Interestingly, microarray gene analysis has identified a gene signature that was able to predict response to dasatinib in cell lines from breast,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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