Roles and inhibitors of FAK in cancer: current advances and future directions

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.

Keywords: IN10018; defactinib; drug resistance; focal adhesion kinase; immune microenvironment; inhibitor; signal pathway.

FIGURE 1

FAK domain structure. FAK consists of a central kinase domain flanked by a FERM homology domain on the N-terminal side and a C-terminal FAT domain. Both the terminal domains are separated from the kinase domain by a linker region containing proline-rich regions (PRR). Important tyrosine (Y) phosphorylation (P) sites are indicated; Y397, K454, and H58 play crucial roles in FAK activation. FAK binding partners are displayed at their interaction sites within FAK. The color signifies the function of FAK interacting proteins, which facilitate diverse activities of cancer cells by interacting with FAK (Sulzmaier et al., 2014).

FIGURE 2

The regulatory mechanism of FAK in tumorigenesis, metastasis and angiogenesis. FAK promotes oncogenesis by activating transcription factors via the p53, YAP, RAS/RAF/MEK/ERK, PI3K/AKT, and downstream pathways including mTOR, β-catenin, or JNK.

FIGURE 3

The role of FAK in tumor microenvironment (TME). The abnormal activation of FAK inhibits T cells, B cells, and dendritic cells (DCs) in the immune microenvironment. Furthermore, the activation of FAK leads to the promotion of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and angiogenesis, all of which contribute to the progression of the tumors. FAK inhibitors, when combined with PD-1/PD-L1 inhibitors, demonstrate a more powerful anti-tumor effect by blocking tumor growth and enhancing immune cell functionality. ECM, extracellular matrix.

FIGURE 4

The chemical structure of FAK inhibitors IN10018, defactinib, GSK2256098, conteltinib, and APG-2449.

FIGURE 5

FAK- PROTAC domain structure and working principle. The FAK-PROTAC system comprises three essential components: a specifically designed warhead to bind to FAK, an E3 ubiquitin ligand responsible for recruiting E3 ubiquitin ligase, and a linker connecting the two. PROTAC functions by facilitating the proximity between FAK and E3 ubiquitin ligase, which subsequently leads to ubiquitination, followed by proteasome degradation. PROTAC: Proteolysis Targeting Chimera.