PTK2

Detailed Information

The PTK2 (Protein Tyrosine Kinase 2) gene is located on human chromosome 8q24.3 and encodes a cytoplasmic non-receptor tyrosine kinase known as focal adhesion kinase (FAK). Alternative splicing of this gene generates multiple transcript variants encoding distinct isoforms, among which the full-length FAK protein of approximately 125 kDa and the C-terminal truncated regulatory isoform FRNK (FAK-related non-kinase) are the most notable. Structurally, FAK contains three essential functional domains: the N-terminal FERM domain (4.1 protein–ezrin–radixin–moesin), which mediates interactions with membrane receptors and signaling proteins; the central tyrosine kinase domain, which catalyzes phosphorylation reactions; and the C-terminal focal adhesion targeting (FAT) domain, which localizes FAK to adhesion complexes. The tyrosine residue at position 397 (Y397) within the kinase domain is the critical autophosphorylation site, whose phosphorylation induces conformational changes that expose binding sites for SRC family kinases, leading to the formation of the FAK-SRC signaling complex. This complex acts as a central hub for FAK signaling, phosphorylating downstream substrates and initiating multiple signaling cascades.

Figure 1. Schematic representation of FAK structure. (Yang M, et al., 2024)

FAK is highly conserved across evolution, with more than 90% sequence homology between species, reflecting its fundamental role in cellular biology. Although belonging to the FAK subfamily, its sequence similarity with other tyrosine kinase subfamily members is relatively limited, giving it unique structural characteristics. In normal tissues, FAK is expressed at low basal levels and primarily regulates adhesion dynamics between cells and the extracellular matrix. In pathological conditions, particularly in cancers, its expression is markedly elevated and it functions as a key driver of tumor invasion and metastasis.

Biological Functions and Signaling Networks

FAK plays a central role in regulating interactions between cells and the extracellular matrix. It localizes within focal adhesion complexes and functions as a crucial downstream signaling hub of integrins, coordinating adhesion, spreading, migration, proliferation, and survival. Upon integrin engagement with extracellular matrix components, FAK undergoes rapid autophosphorylation at Y397. This event not only enhances FAK’s kinase activity but also provides a binding site for SRC family kinases, leading to the formation of the FAK-SRC signaling complex. This complex can further phosphorylate multiple tyrosine residues on FAK (such as Y576/Y577 and Y925), generating a platform that recruits adaptor proteins like Grb7 and p130Cas, as well as effector proteins such as PI3K, thereby activating multiple downstream pathways.

Through phosphorylation of cytoskeletal proteins such as paxillin and talin, FAK regulates the assembly and disassembly of focal adhesions and modulates actin cytoskeleton remodeling, which determines cellular motility and migration modes. At the level of Rho family GTPases (including Rac1 and RhoA), FAK regulates guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), fine-tuning directional and persistent migration. In proliferative and survival signaling, FAK activates the PI3K-AKT pathway and MAPK cascades, particularly ERK1/2, to promote cell cycle progression and suppress apoptosis. Notably, FAK can also translocate to the nucleus, where it interacts with the ubiquitin ligase MDM2 to promote p53 ubiquitination and degradation, thereby attenuating cell cycle checkpoint control.

During embryonic development, FAK is essential for vascular formation and nervous system development. Gene knockout studies show that FAK deficiency causes embryonic lethality due to defects in angiogenesis and neurodevelopment, underscoring its indispensable developmental role. In adult tissues, however, excessive FAK activation is often associated with pathological processes, particularly tumor progression and metastasis, where FAK integrates mechanical and biochemical cues from the tumor microenvironment to promote invasive phenotypes.

Central Role in Tumor Metastasis

FAK overexpression and aberrant activation are common in multiple epithelial cancers such as lung, gastric, colorectal, uterine cancers, and melanoma. Its expression is strongly associated with metastatic potential and poor prognosis. At the initiation of metastasis, FAK overexpression weakens cell–cell and cell–matrix adhesion, facilitating detachment from the primary site. In extracellular matrix degradation, FAK promotes secretion and activation of matrix metalloproteinases (MMPs), enabling basement membrane and stromal breakdown. During migration and invasion, FAK orchestrates lamellipodia and invadopodia formation at the leading edge, guiding directional tumor cell movement toward vasculature and lymphatics.

Clinical studies indicate that high FAK expression correlates with shorter median survival, and its levels can serve as an independent prognostic marker of metastatic potential. Mechanistically, FAK promotes epithelial–mesenchymal transition (EMT) by downregulating epithelial markers such as E-cadherin and upregulating mesenchymal markers like vimentin, enhancing motility and plasticity. It also regulates chemokine receptor expression, sensitizing tumor cells to environmental cues and directing organ-specific metastasis. In circulation, FAK activation of PI3K-AKT signaling helps tumor cells resist anoikis and hemodynamic stress. During colonization, FAK promotes adhesion to microvascular endothelium, transendothelial migration, and evasion of immune surveillance.

Importantly, FAK signaling within the tumor microenvironment extends beyond tumor cells. In cancer-associated fibroblasts (CAFs), it promotes secretion of pro-tumorigenic factors and extracellular matrix remodeling. In endothelial cells, FAK regulates angiogenesis, while in immune cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), it contributes to establishing an immunosuppressive microenvironment that facilitates tumor immune evasion and metastatic spread.

Inhibitor Development and Clinical Translation

Given its central role in tumor progression, FAK has become a therapeutic target of interest. Strategies under investigation include small-molecule ATP-competitive inhibitors, allosteric inhibitors, and protein–protein interaction inhibitors. Compounds such as PF-228 and PF-271 (Pfizer), and VS-6063 (defactinib) and VS-4718 (GlaxoSmithKline), have shown efficacy in preclinical models, reducing migration and invasion by blocking ATP binding in the kinase domain.

Phase I clinical trials demonstrated the safety of FAK inhibitors as monotherapies, with most adverse events being mild to moderate, including fatigue, gastrointestinal reactions, and reversible hypertension, with no dose-limiting toxicities observed. However, clinical efficacy as monotherapy has been modest, with objective response rates of about 27%. This limitation reflects the fact that FAK is not typically an oncogenic driver mutation but rather a facilitator of tumor progression. Consequently, research focus has shifted to combination strategies, particularly with inhibitors of driver oncogenes.

One of the most promising strategies is the combination with KRAS inhibitors. In KRAS-mutant cancer models, the FAK inhibitor IN10018 (originally developed by Boehringer Ingelheim and later acquired by InxMed) demonstrated strong synergy with the KRASG12C inhibitor sotorasib, suggesting bidirectional crosstalk between FAK and RAS-MAPK signaling. Combination therapy suppressed primary tumor growth and effectively blocked metastatic progression, with clinical trials currently ongoing in China.

Beyond small molecules, newer approaches are being explored, such as FAK-targeting PROTACs, inhibitors of FAK-SRC interactions, and gene silencing strategies. PROTACs such as GSK215 showed greater efficacy in preclinical studies than conventional inhibitors by degrading FAK and eliminating its kinase-independent scaffold functions. In addition, targeting stromal FAK in CAFs may improve tumor drug penetration and sensitize tumors to chemotherapy.

Challenges and Future Directions

Despite encouraging progress, several challenges remain in developing FAK-targeted therapies. FAK’s fundamental role in normal tissues, particularly in cardiovascular and nervous systems, poses toxicity risks that require careful therapeutic window management. The heterogeneity of metastasis highlights the need for predictive biomarkers such as FAK gene amplification, Y397 phosphorylation, or specific transcriptional signatures to identify patients most likely to benefit. Optimal combination regimens also require systematic evaluation, including combinations with immune checkpoint inhibitors, anti-angiogenic therapies, and epigenetic modulators.

Figure 2. Model showing FAK activation sustaining tumor sphere growth and chemotherapy resistance in high-grade serous ovarian cancer. (Dawson JC, et al., 2021)

Resistance mechanisms also pose a challenge, as compensatory activation of signaling pathways such as IGF1R or EGFR has been observed following FAK inhibition, underscoring the need for multi-targeted approaches. Furthermore, FAK’s role in regulating tumor mechanical properties suggests that its inhibition may overcome therapy resistance driven by tissue stiffness, improving drug penetration and immune response. Finally, the development of FAK inhibitors capable of crossing the blood–brain barrier will be important for targeting brain metastases.