Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

Abstract

Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors.

Mycobacterium tuberculosis Exploits Focal Adhesion Kinase to Induce Necrotic Cell Death and Inhibit Reactive Oxygen Species Production

“…PF-562-271 is a methane sulphonamide diaminopyrimidine developed by Pfizer ( 68 ). A second generation of this inhibitor named VS-6063 (defactinib) is currently in phase I and II clinical trials for the treatment of various cancers in combination with immunotherapies and other small molecule inhibitors ( 71 ). The potential cytotoxicity of the mouse-specific FAK inhibitor PF-562-271 was assessed on RAW 264.7 cells ( Figure 2E ).…”

CXCR6-CXCL16 Axis Promotes Breast Cancer by Inducing Oncogenic Signaling

“…Specifically, Src, FAK, ERK1/2, and PI3K/Akt pathways were activated after the CXCR6 stimulation of BrCa cells. These pathways cumulatively affect the metastatic potential of cells by reorganizing actin polymerization, migratory capacity, and basement membrane invasion [ 25 , 26 , 27 , 28 ].…”

Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma

“…In concert with integrin-mediated signaling a function in invasion and metastatic characteristics of the epithelial-mesenchymal transition has been attributed to FAK [ 13 , 15 ]. Likewise, increased FAK expression has been implemented in survival of other cancer types, including breast cancer [ 36 , 37 ], bladder cancer [ 38 ] and squamous cell carcinoma [ 39 ] through activation of MAPK- and PI3K-related signaling pathways [ 40 ]. Following this line, we show that MM cells that had acquired resistance to IZI1551, presented with increased integrin αVβ3 expression and consequently constitutive FAK activation, followed by downstream activation of MAPK and PI3K-driven survival pathways.…”