Targeting focal adhesion kinase in cancer cells and the tumor microenvironment

Abstract

Focal adhesion kinase (FAK) is an integrin-associated protein tyrosine kinase that is frequently overexpressed in advanced human cancers. Recent studies have demonstrated that aside from FAK’s catalytic activity in cancer cells, its cellular localization is also critical for regulating the transcription of chemokines that promote a favorable tumor microenvironment (TME) by suppressing destructive host immunity. In addition to the protumor roles of FAK in cancer cells, FAK activity within cells of the TME may also support tumor growth and metastasis through various mechanisms, including increased angiogenesis and vascular permeability and effects related to fibrosis in the stroma. Small molecule FAK inhibitors have demonstrated efficacy in alleviating tumor growth and metastasis, and some are currently in clinical development phases. However, several preclinical trials have shown increased benefits from dual therapies using FAK inhibitors in combination with other chemotherapies or with immune cell activators. This review will discuss the role of nuclear FAK as a driver for tumor cell survival as well as potential therapeutic strategies to target FAK in both tumors and the TME.

Divergent molecular signatures of regeneration and fibrosis during wound repair

“…Fibrotic trajectory cells also had increased expression of Fgf2, Il6, Ccl2, Sox9, and Myc, whose upregulation in fibroblasts has been implicated in focal adhesion kinase (FAK)-mediated organ fibrosis and tumor stroma deposition. (Murphy et al, 2020;Wong et al, 2011) Gene set enrichment analysis on the top 1% of genes positively correlated with pseudotime revealed terms related to ECM deposition (e.g., ECM structural constituent, GAG binding), growth factor production/activity, and mechanotransduction signaling We next examined the genes most strongly anticorrelated with this pseudotime trajectory. Interestingly, consistent with the more regenerative phenotype whose cells were over-represented along this branch, we identified multiple genes involved in developmental and regenerative pathways (Figure 2E, Figure S7C).…”

The fibrotic and immune microenvironments as targetable drivers of metastasis

“…For example, the importance of focal adhesion kinase (FAK) within the tumour cell compartment in driving tumour proliferation and metastasis is well documented and has led to the development of a number of small-molecule inhibitors, which are currently under clinical evaluation. 100 Interestingly, fibroblast-directed deletion of FAK, in a genetically engineered mouse model of breast cancer, reduced metastasis but had no effect on primary tumour growth. Mechanistically, this result was attributed to the secretion from FAK-deficient CAFs of exosomes enriched with the tumour-suppressive microRNAs miR-16 and miR-148a, which suppressed an EMT and migratory phenotype in the cancer cells.…”

High Cytoplasmic and Membranous Versus Nuclear Talin-1 Expression Associated With Malignancy Potential and Determine Survival and Metastasis of Clear Cell Renal Cell Carcinoma

“…Since FAK functions potentially regulate gene expression to affect cancer progression (43), it seems that its signaling to be vital in the neoplastic cells invasion, and its activity inhibition decrease RCC metastasis both in vitro and in vivo (44)(45)(46). Although the FAK signaling pathway is deregulated in different cancer types and its importance approved in the regulation of cell adhesion and motility due to the tumor invasive behavior (47)(48)(49), its evidence in RCC is few and it is necessary to explore which is crucial (42). Further, UALCAN database revealed a higher expression of Talin-1 protein in ccRCC tissue samples compared to normal samples ( Fig.…”