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

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.

ADAM15 Protein Amplifies Focal Adhesion Kinase Phosphorylation under Genotoxic Stress Conditions

“…The novel function of ADAM15 elucidated in chondrocytic cells under genotoxic stress as a model mimicking the proapoptotic milieu in OA cartilage might also be relevant beyond its homeostatic role in cartilage degeneration to other pathologic conditions such as neoplastic disease. This is in compliance with already published evidence in the latter conditions (2,40,41) incriminating ADAM15 expression and FAK-Src complex activation in aggressive malignant growth.…”

LAMC2 enhances the metastatic potential of lung adenocarcinoma

“…Evidence suggests that FAK and SRC, through integrating intracellular signals, activate EMT regulators, ZEB1 and Snail. 43 It is possible that the elevated LAMC2 in cancer cells may, through interaction with integrin β1, hijack part of the focal adhesion complex including FAK/SRC kinase 44 to induce EMT via ZEB1 and/or Snail.…”

Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

“…In addition, assembling of the focal adhesion complex is able to activate a number of signaling pathways to regulate cell activities. 10,11 Stiff matrices increase the number of focal adhesions (FAs) and traction force generated between FAs and the ECM compared to soft ones. A FA complex in a cell functions as a mechanosensor that generates a fluctuating force to pull the ECM, thereby directing cells to migrate to an area with greater ECM stiffness.…”