New Insights on the Nuclear Functions and Targeting of FAK in Cancer

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different ways: a kinase activity in the cytoplasm, mainly dependent on the integrin signaling, and a scaffolding activity into the nucleus by networking with different gene expression regulators. For this reason, FAK has to be considered a target with high therapeutic values. Indeed, evidence suggests that FAK targeting could be effective, either alone or in combination, with other already available treatments. Here, we propose an overview of the novel insights about FAK’s structure and nuclear functions, with a special focus on the recent findings concerning the roles of this protein in cancer. Additionally, we provide a recent update on FAK inhibitors that are currently in clinical trials for patients with cancer, and discuss the challenge and future directions of drug-based anti-FAK targeted therapies.

High expression of phosphorylated focal adhesion kinase predicts a poor prognosis in human colorectal cancer

“…FAK signaling pathway is a key role in driving cell functions regulated by integrins and growth receptor factors ( Mohanty et al, 2020 ; Chuang et al, 2022 ). Overexpression of FAK and p-FAK in numerous cancers indicates that targeting FAK might be effective in suppressing biological capacities required for tumorigenesis which makes it an attractive drug target for anti-cancer therapy ( Sharma et al, 2017 ; Pomella et al, 2022 ). The inhibitors blunt FAK Try-397 auto-phosphorylation and affects downstream signaling pathways including PI3K/AKT, STAT3 and JNK in some cancer cells, and further influence cell viability, proliferation, migration, and immunosuppressive TME ( Zhang et al, 2014 ; Hirt et al, 2018 ).…”

“…It is reported that activated FAK regulated Y-box binding protein 1 to induce paclitaxel resistance in ovarian cancer while FAK inhibitor could reduce the resistance ( Kang et al, 2013 ). Currently, a big effort in several Phase I and II clinical trials have been activated to evaluate the efficacy of FAK inhibitors in cancer treatment as single agents or in combination with chemotherapy ( Pomella et al, 2022 ). FAK inhibitors may become effective in reversing insensitive chemotherapy response for early-stage CRC patients with high p-FAK expression that remains future studies.…”

Radioresistance in rhabdomyosarcomas: Much more than a question of dose

“…Thus, it seems unlikely that DNA-PKcs targeting will not lead to an RMS radiosensitization. Notably, several molecules have been identified as upstream regulators of DDR in RMS including ERKs ( 126 , 129 ), DNA methyltransferases 3A (DNMT3A) and DNMT3B ( 130 ), BET proteins ( 131 ), ephrin-A2 ( 132 ), caveolin-1 (CAV-1) ( 128 ), nuclear factor erythroid 2–related factor 2 (NRF-2) ( 133 ), c-Myc ( 116 ), SNAI2 ( 134 ), FAK ( 135 ), androgen receptor ( 136 ), and HDAC ( 137 – 139 ). Thus, another strategy to target DDR could be inhibiting these upstream molecules.…”

3D-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors

“…Overexpression of the FAK receptor is known for its pivotal role in cell division, proliferation, migration, adhesion, and angiogenesis through its enzymatic activities in different types of cancer progression in humans [1]. FAK, also known as protein tyrosine kinase 2 (PTK2), comprises an N-terminal four-point-one, ezrin, radixin, moesin (FERM) domain, a catalytic kinase domain, and a C-terminal domain (Fig 1) [2]. The FERM domain is further divided into smaller subdomains (F1, F2, and F3), directly bound to the intercellular part of the transmembrane receptor proteins and the binding site for the growth factor receptors, C-Met, p53, and mouse double minute 2 (MDM2) proteins [3].…”