Targeting focal adhesion kinase in cancer cells and the tumor microenvironment

Focal adhesion kinase (FAK) is an integrin-associated protein tyrosine kinase that is frequently overexpressed in advanced human cancers. Recent studies have demonstrated that aside from FAK's catalytic activity in cancer cells, its cellular localization is also critical for regulating the transcription of chemokines that promote a favorable tumor microenvironment (TME) by suppressing destructive host immunity. In addition to the protumor roles of FAK in cancer cells, FAK activity within cells of the TME may also support tumor growth and metastasis through various mechanisms, including increased angiogenesis and vascular permeability and effects related to fibrosis in the stroma. Small molecule FAK inhibitors have demonstrated efficacy in alleviating tumor growth and metastasis, and some are currently in clinical development phases. However, several preclinical trials have shown increased benefits from dual therapies using FAK inhibitors in combination with other chemotherapies or with immune cell activators. This review will discuss the role of nuclear FAK as a driver for tumor cell survival as well as potential therapeutic strategies to target FAK in both tumors and the TME. Cancer treatment: Targeting more than just the tumor Targeting a signal protein in the tumor microenvironment (TME), the tissues surrounding tumors, as well as in the tumor itself may lead to more effective cancer treatments. High levels of the signal protein FAK are associated with many tumors. A pro-tumor function of FAK has recently also been reported from the TME, which can strongly influence treatment outcome. Ssang-Taek Steve Lim at the University of South Alabama, Mobile, USA, and co-workers have reviewed the functions of FAK in tumors and the TME. They report that FAK increases development and permeability of blood vessels in the TME, feeding the tumor and permitting cancer cells to travel to other locations. FAK also protects tumors from the immune response and from chemotherapy. These results point the way to treatments potentially effective against many types of cancer.