Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

Abstract

Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting. In addition, the effects of chemotherapy are nonspecific, targeting both malignant and normal tissues. As a result, recent efforts increasingly have focused on developing agents that target specific molecules in tumor cells in order to both improve efficacy and limit toxicity. This review summarizes the history and current use of targeted molecular therapy for cancer, with a special emphasis on recently developed inhibitors of Focal Adhesion Kinase (FAK).

Emerging Roles of Focal Adhesion Kinase in Cancer

“…Cell proliferation is a process of the increment of cell number as a result of cell division and growth. Discovery of the expression and tyrosine phosphorylation of FAK highly correlated with cell cycle progression by modulating cell cycle-relative molecules [ 31 ] highlights FAK functioning as a key regulator in promoting cancer proliferation. Eventually, overexpression of FAK enables increasing cyclin D1 expression and decreasing cyclin-dependent kinase (CDK) inhibitor p21 expression, thereby accelerating G1 to S-phase transition.…”

The FAK inhibitor BI 853520 exerts anti-tumor effects in breast cancer

“…Every year, more than 1.4 million women worldwide are diagnosed with breast cancer, and over 450,000 women will lose their lives to this disease, mostly due to metastasis 1 . Over the past decades, we have gained many important insights into breast cancer biology, which in turn have allowed the development of therapeutic approaches targeting molecules and signaling pathways specifically present in breast cancer cells 2 , 3 . Previous studies have linked the overexpression and activation of focal adhesion kinase (FAK) with the initiation and progression of a wide variety of malignancies, such as ovarian, head and neck, and breast carcinoma 2 – 6 .…”

Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways

“…Increased FAK expression and tyrosine phosphorylation have been observed in many malignant human tumors, and elevated expression of FAK is correlated with poor prognosis [12–14]. The inhibition of FAK functionality by small molecules reduced both the motility and viability of cancer cells in both mouse models and human clinical trials [15–17], suggesting that FAK might be a potential therapeutic target to treat highly invasive types of cancers. The COOH-terminal domain of FAK interacts with integrin-associated proteins; for example, FAK is activated upon cell binding to ECM proteins and forms a transient signaling complex with the steroid receptor coactivator (Src) family of protein tyrosine kinases [18].…”