Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Abstract

Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.

Keywords: focal adhesion kinase; small-cell lung cancer; targeted therapy.

Figure A1

PRISMA guidelines for methodological review of literature related to frequency of focal adhesion kinase (FAK) overexpression at protein level in human solid cancers.

Figure 1

The domain organization and activation of focal adhesion kinase (FAK). FAK is composed of a central kinase domain (KD), an amino-terminal side that is flanked by a protein band 4.1-ezrin-radixin-moesin (FERM) homology domain, and a carboxy-terminal focal adhesion targeting (FAT) domain flanked by proline-rich regions (PRRs). FAK localizes to focal adhesions and is triggered off by extracellular signals such as integrin-mediated adhesion and some growth factors. FAK is maintained in an inactive state by the binding of the FERM domain to the kinase domain, which blocks access to the catalytic site and sequesters the activation loop, as well as the key autophosphorylation site tyrosine 397 (Tyr397). Engagement of integrins with the extracellular matrix (ECM) or growth factors leads to signals that displace the FERM domain, resulting in rapid autophosphorylation of Tyr397, which is a critical event in signal transduction by FAK.

Figure 2

Frequency of focal adhesion kinase (FAK) overexpression at protein level in human solid cancers. A Pubmed search of studies evaluating FAK protein expression in human cancers by immunohistochemistry (IHC) was performed to determine the percentage of cancer samples with increased FAK protein expression. The following keywords were used in the search strategy: FAK [All Fields] AND (“neoplasms” [MeSH Terms] OR “neoplasms” [All Fields] OR “cancer” [All Fields]) AND (“immunohistochemistry” [MeSH Terms] OR “immunohistochemistry” [All Fields]). The results were limited to English language studies. Manual searches of reference articles from applicable studies were performed to identify articles that may have been missed by the computer-assisted search. Abstracts were excluded for cell lines, pre-invasive tumors, if insufficient data to evaluate the methodological quality, absence of tumor total FAK staining, absence of FAK quantification or proportion, absence of proportion of samples overexpressing FAK. Non-eligible trials included ecological studies, case reports, reviews, editorials, and animal trials. This work was conducted in accordance with the PRISMA guidelines (Figure A1). N = number of cancers analysed.

Figure 3

(A) Frequency of increased focal adhesion kinase (FAK) expression at mRNA levels in human cancers. The Cancer Genome Atlas (TCGA) was queried using cbioportal.org to determine the percentage of tumor samples with increased levels of FAK mRNA expression. Search criteria included mRNA expression data (Z-scores for all genes) and tumor datasets with mRNA data. N = number of cancers analysed in the TCGA. (B) Frequency of focal adhesion kinase (FAK) genomic alterations in human cancers. The Cancer Genome Atlas (TCGA) was queried using cbioportal.org to determine the percentage of samples with FAK genomic alterations (mutations, fusions, amplifications, deep deletions, multiples alterations) in different cancers. Search criteria included PTK2 (FAK). N = number of cancers analysed in the TCGA.

Figure 4

Pro-tumoral functions of FAK. (A). FAK is triggered off by integrins, G protein-coupled receptors (GPCR), growth factor receptors, and vascular endothelial growth factor receptor (VEGFR). Activated FAK promotes cell proliferation and survival. FAK also contributes to tumor progression and metastasis via cell adhesion, migration, and promotion of epithelial to mesenchymal transition (EMT). Transient contact between platelets and tumor cells induces TGFβ production by the platelets, which promotes EMT-like transformation and invasive behaviour. In endothelial cell (EC), FAK drives angiogenesis, increases vascular permeability, and regulates platelet extravasation; this facilitates intravasation or extravasation of tumor cells, leading to metastasis. Additionally, FAK induces a tumor protective fibrotic and immunosuppressive tumor microenvironment that promotes antitumor immune evasion. Indeed, FAK induces cytokines (short soluble (sST2), IL33, Ccl5), which lead to the recruitment of immunosuppressive cells, such as regulatory T cells (Treg), tumor-associated macrophages (TAM), and GR1+ granulocytes, as well as to increased tumor fibrosis. Pro-tumoral functions of FAK. (B). Ionizing radiations, chemotherapy, and reactive oxygen species (ROS) increase DNA damage and activate FAK in tumor cells. Activated FAK favors the expression of DNA damage repair (DDR) genes such as Growth Arrest and DNA Damage-inducible 45 (GADD45), Ataxia Telangiectasia Mutated (ATM) genes, and Ataxia Telangiectasia and Rad3-related (ATR) genes which play an important role in resistance to drug and radiation. Additionally, in endothelial cells (EC), ionizing radiations activate FAK and NF-kB, which induces the production of various cytokines (IL-1α, IL-2, IL-4 IL-6, IL-16) activating the proliferation of tumor cells. Abbreviations used in the figure and not described in the legend: IL-1RAcP: interleukin-1 receptor accessory protein, ST2L: longer membrane bound form.

Figure 5

Association of focal adhesion kinase (FAK) amplification with survival. Kaplan-Meier overall survival and progression-free survival analysis of patients with versus without FAK amplification in their tumors (many different cancers included) in The Cancer Genome Atlas (TCGA) database [110].