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ABSTRACT
Introduction
FAK, a nonreceptor cytoplasmic tyrosine kinase, plays a crucial role in tumor metastasis, drug resistance, tumor stem cell maintenance, and regulation of the tumor microenvironment. FAK has emerged as a promising target for tumor therapy based on both preclinical and clinical data.
Areas covered
This paper aims to summarize the molecular mechanisms underlying FAK’s involvement in tumorigenesis and progression. Encouraging results have emerged from ongoing clinical trials of FAK inhibitors. Additionally, we present an overview of clinical trials for FAK inhibitors, examining their potential as promising treatments. The pertinent studies gathered from databases including PubMed, ClinicalTrials.gov.
Expert opinion
Since the first finding in 1990s, targeting FAK has became the focus of interests in many pharmaceutical companies. Through 30 years’ discovery, the industry and academy gradually realized the features of FAK target which may not be a driver gene but a solid defense system for the cancer initiation and development. Currently, the ongoing clinical regimens involving FAK inhibition are all the combination strategies in which FAK inhibitors can further strengthen the cancer cell killing effects of other testing agents. The emerging positive signal in clinical trials foresee targeting FAK as class will be an effective mean to fight against cancers.
Article highlights
FAK plays an important role in tumor cell migration and stemness.
FAK plays a key role in tumor drug resistance.
In EMT and TME processes, FAK plays an important role.
Summary of FAK inhibitors in pre-clinical and in clinical trials.
FAK inhibitors show potential in combination with multiple therapies, promising for advanced cancers.
Abbreviations list
| FAK | = | Focal adhesion kinase |
| SRC oncogene | = | Src proto-oncogene, non-receptor tyrosine kinase |
| Y397 | = | Autophosphorylation site tyrosine 397 |
| SH2 | = | Src Homology 2 |
| mRNA | = | Messenger Ribonucleic Acid |
| Rho family | = | Ras homolog gene family, member A/B/C/D/E. |
| GTPases | = | Guanosine triphosphate hydrolases |
| p190RhoGEF | = | p190 Rho guanine nucleotide exchange factor |
| Cas | = | Crk-associated substrate |
| Crk | = | Cytokine Receptor Kinase |
| MMPs | = | Matrix metalloproteinases |
| ERK | = | Extracellular regulated protein kinases |
| ECM | = | Extracellular matrix |
| MAPK | = | Mitogen-activated protein kinase |
| miR-7 | = | MicroRNA-7 |
| NSCLC | = | Non-small cell lung cancer |
| AKT | = | Protein Kinase B |
| NF-κB | = | Nuclear factor kappa-B |
| CSCs | = | Cancer stem-like cells |
| Wnt | = | Wingless-Int-1 |
| PI3K | = | Phosphoinositide 3-kinase |
| GC | = | Gastric cancer |
| CAFs | = | Cancer-associated fibroblasts |
| PDPN | = | Podoplanin |
| POSTN | = | Periostin |
| YAP | = | Yes-associated protein |
| MOB1 | = | MOB kinase activator 1 |
| LATS1/2 | = | Large Tumor Suppressor Kinase 1/2 |
| BRAF | = | B-Raf proto-oncogene, serine/threonine kinase |
| TAZ | = | PDZ-binding motif |
| MEK | = | Mitogen-activated extracellular signal-regulated kinase |
| KRAS | = | Kirsten ratsarcoma viral oncogene homolog |
| ROS1 | = | ROS proto-oncogene 1， receptor tyrosine kinase |
| DGC | = | Diffuse gastric cancer |
| TRX | = | Thioredoxin |
| MDR | = | Multidrug resistance |
| ABC | = | Adenosine triphosphate binding cassette |
| ABCB1 | = | Adenosine triphosphate -binding cassette sub-family B member 1 |
| ABCG2 | = | Adenosine triphosphate -binding cassette efflux transporter G2 |
| EMT | = | Epithelial-Mesenchymal Transition |
| E-cadherin | = | Epithelial cadherin |
| KIF26A | = | Kinesin Family Member 26A |
| c-MYC | = | Cellular-myelocytomatosis viral oncogene |
| ILK | = | Integrin linked kinase Gene |
| TME | = | Tumor microenvironment |
| CAFs | = | Cancer-associated fibroblasts |
| EVs | = | Extracellular vesicles |
| Protac | = | Proteolysis-targeting chimeras |
| SCC | = | Squamous cell carcinoma |
| Ccl5 | = | C-C motif chemokine ligand 5 |
| TGFβ2 | = | Transforming growth factor-β |
| IL33 | = | Interleukin 33 |
| ST2 | = | Growth stimulation expressed gene 2 |
| PDAC | = | Pancreatic ductal adenocarcinoma |
| Psmb8 | = | Proteasome 20S subunit beta 8 Gene |
| MHC-I | = | Major histocompatibility complex class I |
| STAT | = | Signal transducerand activator of transcription |
| PD-1 | = | Programmed cell death protein 1 |
| EC | = | Endothelial Cell |
| VEGFR2 | = | Vascular Endothelial Growth Factor Receptor 2 |
| FAK CKO | = | Endothelium-specific deletion of FAK in mice |
| VE-cadherin | = | Vascular endothelial cadherin |
| TP53 | = | Tumor protein p53 |
| CDKN2A | = | Cyclin dependent kinase inhibitor 2A Gene |
| BID | = | Bis in die |
| LGSOC | = | Low-grade serous ovarian cancer |
| PROC | = | Platinum-resistant ovarian cancer |
| TNBC | = | Triple-negative breast cancer |
| CR | = | Complete response |
| PR | = | Partial response |
| ORR | = | Overall response rate |
| DCR | = | Disease control rate |
| mPFS | = | Median progression-free survival |
| mOS | = | Median overall survival |
| SD | = | Stable disease |
| PFI | = | Progression Free Interval |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgments
We appreciate Yinxing Zhu’s proofreading of the drug clinical trial section of this article and Ran Pang and Shuang Xie’s valuable comments on this article.