The dual kinase complex FAK-Src as a promising therapeutic target in cancer

Victoria Bolós^1,*, Joan Manuel Gasent^2,*, Sara López-Tarruella³, Enrique Grande^1,#

¹Pfizer Oncology, Madrid, Spain; ²Hospital Gral. Universitario Marina Alta, Oncology Department, Denia Alicante, ^3,#Hospital Clínico San Carlos, Oncology Department, ∗These authors contributed equally to this work, ^#Center affiliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021). Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation

Abstract: Focal adhesion kinase (FAK) and steroid receptor coactivator (Src) are intracellular (nonreceptor) tyrosine kinases that physically and functionally interact to promote a variety of cellular responses. Plenty of reports have already suggested an additional central role for this complex in cancer through its ability to promote proliferation and anoikis resistance in tumor cells. An important role for the FAK/Src complex in tumor angiogenesis has also been established. Furthermore, FAK and Src have been associated with solid tumor metastasis through their ability to promote the epithelial mesenchymal transition. In fact, a strong correlation between increased FAK/Src expression/phosphorylation and the invasive phenotype in human tumors has been found. Additionally, an association for FAK/Src with resistances to the current anticancer therapies has already been established. Currently, novel anticancer agents that target FAK or Src are under development in a broad variety of solid tumors. In this article we will review the normal cellular functions of the FAK/Src complex as an effector of integrin and/or tyrosine kinase receptor signaling. We will also collect data about their role in cancer and we will summarize the most recent data from the FAK and Src inhibitors under clinical and preclinical development. Furthermore, the association of both these proteins with chemotherapy and hormonal therapy resistances, as a rationale for new combined therapeutic approaches with these novel agents, to abrogate treatment associated resistances, will also be reviewed.

Keywords: SRC, FAK, cancer, therapeutic target, FAK inhibitors, SRC inhibitors