FAK in Cancer: From Mechanisms to Therapeutic Strategies

Abstract

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is overexpressed and activated in many cancer types. FAK regulates diverse cellular processes, including growth factor signaling, cell cycle progression, cell survival, cell motility, angiogenesis, and the establishment of immunosuppressive tumor microenvironments through kinase-dependent and kinase-independent scaffolding functions in the cytoplasm and nucleus. Mounting evidence has indicated that targeting FAK, either alone or in combination with other agents, may represent a promising therapeutic strategy for various cancers. In this review, we summarize the mechanisms underlying FAK-mediated signaling networks during tumor development. We also summarize the recent progress of FAK-targeted small-molecule compounds for anticancer activity from preclinical and clinical evidence.

Keywords: combination therapy; drug resistance; focal adhesion kinase; metastasis; tumor microenvironment.

Figure 1

Protein structure and multiple binding partners of focal adhesion kinase. Focal adhesion kinase (FAK) is composed of an amino-terminal region containing a protein band 4.1–ezrin–radixin–moesin (FERM) domain, followed by a central kinase domain and a carboxy-terminal focal adhesion targeting (FAT) domain. Three proline-rich regions (PRRs) are embedded in the linker regions between these domains. Tyr397, Lys454, and His58 are important for FAK activation. Phosphorylation (P) occurs on several important tyrosine residues, as indicated, including the autophosphorylation site Tyr397, the Tyr576/577 residues in the activation loop of the kinase domain, and Tyr861, Tyr925, and Tyr1007 in the C-terminal domain. There are one nuclear export signal (NES) sequence and one nuclear localization signal (NLS) sequence in the FERM domain of FAK and one NES sequence in the kinase domain. Many proteins bind to FAK, regulating its functions or forming a complex, which is necessary for distinct biological processes. Phosphorylated Tyr397 is a well-known binding site for Src homology 2 (SH2) domain-containing proteins. The PRRs provide proline-rich sequences that bind with Src homology 3 (SH3) domain-containing proteins. The FAT domain is required to target FAK to the focal adhesion via binding to talin and paxillin.

Figure 2

FAK-mediated signaling cascades involved in tumor progression. Focal adhesion kinase (FAK) is activated by Integrins, receptor tyrosine kinases (RTKs), cytokine receptors, G protein-coupled receptors (GPCRs), and changes in the intracellular pH (H⁺). FAK transmits upstream stimuli to downstream effectors through kinase-dependent and -independent signaling cascades, contributing to many biological processes involved in tumorigenesis, such as survival and proliferation, invasion and metastasis, angiogenesis, and immunosuppression.

Figure 3

FAK inhibition serves as a potential cancer treatment strategy. Focal adhesion kinase (FAK) supports myriad oncogenic processes, and targeting FAK suppresses multiple critical biological capacities, such as survival and proliferation, drug resistance, metastasis, angiogenesis, mechanotransduction, and the establishment of an immunosuppressive tumor microenvironment to promote tumor progression.