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Activation of an RTK induces dimerization and downstream phosphorylation of nonreceptor tyrosine kinases. Major signaling cascades include the RAS/RAF/MAPK pathway, MEK pathway, and the PI3kinase/AKT pathway. (Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer, Zhu & Parada, Nature Reviews Cancer, 2002, 2: 616-626, copyright 2002.)
Source publication
Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is oft...
Context in source publication
Context 1
... of the first classes of molecules to be suggested as a potential target for anticancer therapy was the tyrosine kinases (TKs). As their name implies, these enzymes catalyze the phosphorylation of tyrosine kinase moieties on a variety of other signaling proteins [3]. TKs can be classified as either receptor or non-receptor kinases. Receptor tyrosine kinases (RTKs) are membrane spanning proteins that generally function in pairs. Activation induces dimerization, and dimerization then triggers a phosphorylation cascade involving the cytosolic non-receptor tyrosine kinases ( Fig. 1) [3][4][5][6]. Non-receptor tyrosine kinases relay intracellular signals by additional protein phosphorylation [6]. Many processes involved in tumor progression and metastasis, including proliferation, angiogenesis, migration and cell survival, are influenced by activation of RTKs and the subsequent signal cascade [3,5]. Moreover, mutations can alter the expression or activation of TKs and thereby lead to uncontrolled activation in cancer cells [7]. Of the fifty-eight known RTKs, approximately 30% have been found to be either mutated or unregulated in cancer [4,7,8]. In addition, several RTKs are known to play important roles in tumorigenesis, and have become effective therapeutic targets. For example, c-kit is unregulated in gastrointestinal stromal tumors (GISTs) and acute myelogenous leukemia (AML), HER2 is elevated in breast cancer, and RET is altered the MEN disorders [7]. These and other RTKs have long been known to play a role in cancer progression and, as such, inhibition of TKs has been at the forefront of targeted cancer ...
Citations
... Focal adhesion kinase (FAK) is a cytoplasmic molecule that is closely associated with the cell membrane. FAK belongs to the tyrosine kinase family and is an essential mediator of signal transduction pathways and receptor signaling (20) . Upon its activation, subsequent signaling cascades in many cell processes are triggered, including survival signaling, growth, angiogenesis, migration, and invasion (21) . ...
... FAK/PTK2 can also be translocated to the nucleus of cancer cells, where it regulates the expression program of chemokines and cytokines in in ammatory genes [38], so as to promote immune escape and immune therapy resistance [39][40]. Besides, the expression and tyrosine phosphorylation of FAK are highly correlated with cell cycle progression by modulating cell cycle-relative molecules, which highlights that FAK functions as a key regulator in promoting cancer proliferation [41]. Tai YL et al. con rm that FAK activation, as determined by phosphospeci c antibody recognition of the FAK tyrosine autophosphorylation site, is increased with tumor progression [42]. ...
Background: The immune environment in tumors is the key factor affecting the survival and immunotherapeutic response of patients.This research aimed to explore the underlying association between FAK/PTK2 and cancer immunotherapy in 33 human cancers.
Methods: Gene expression data and clinical features of 33 cancers were retrieved from the Cancer Genome Atlas Database. The immunotherapy cohorts included GSE 67501, GSE78220 and IMVIGOR210, which were derived from the comprehensive gene expression database or from previous studies. Clinical parameters including patient age, gender, survival rate and tumor stage were analyzed to evaluate the prognostic value of FAK/PTK2. FAK/PTK2 activity was detected by single-sample gene set enrichment analysis and used to compare the difference between FAK/PTK2 transcriptome and protein expression levels. To better understand the role of FAK/PTK2 in cancer immunotherapy, we analyzed its correlations with tumor microenvironment and with immune processes / elements (e.g. immune cell infiltration, immunosuppressants and stimulants) and major histocompatible complexes. Potential pathways associated with FAK/PTK2 signaling in cancers were also explored. Correlations between FAK/PTK2 and two immunotherapeutic biomarkers (tumor mutation load and microsatellite instability) were studied. Finally, the three independent immunotherapy cohorts were used to study the relationship between FAK / PTK2 and immunotherapeutic response.
Results: Although FAK/PTK2 is not closely associated with age (13/33), gender (5/33) or tumor stage (5/33) in any of the studied human cancers, it has potential prognostic value for predicting patient survival. Consistency between FAK/PTK2 activity and expression exists in some cancers (3/33). Generally, FAK/PTK2 is robustly correlated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Moreover, high FAK/PTK2 expression is significantly related to immune-relevant pathways. However, FAK/PTK2 is not significantly correlated with the immunotherapeutic response.
Conclusions: Research on the immunotherapeutic value of FAK/PTK2 in 33 human cancers provides evidence regarding the function of FAK/PTK2 and its role in clinical treatment. However, given the use of a bioinformatics approach, our results are preliminary and require further validation.
... The F2 subdomain regulates the kinaseindependent activity and mediates cell survival. The F3 subdomain can arrest Mdm-2 to enhance ubiquitination of p53, which alleviates p53 independent cell apoptosis [11,12]. In addition, the key tyrosine residue, Tyr397 is located at the N-terminus end of the FERM structural domain. ...
Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemo-therapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.
... The F2 subdomain regulates the kinaseindependent activity and mediates cell survival. The F3 subdomain can arrest Mdm-2 to enhance ubiquitination of p53, which alleviates p53 independent cell apoptosis [11,12]. In addition, the key tyrosine residue, Tyr397 is located at the N-terminus end of the FERM structural domain. ...
Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.
... Enhanced chemosensitivity to gemcitabine has been reported with interference of FAKs [124]. Because of the involvement of PTK2(FAK) in many cancers, drugs that inhibit FAK are being sought and evaluated [125]. A screen to identify mechanisms of bleomycin resistance identified Sky1, PTK2 and Agp2 as determinants of chemosensitivity [126]. ...
A joint analysis of the NCI60 small molecule screening data, their genetically defective genes, and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-Organizing-Maps (SOMs) are used to organize the chemosensitivity data. Student's t-tests are used to identify SOM clusters with enhanced chemosensitivity for tumor cell lines with versus without genetically defective genes. Fisher's exact and chi-square tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. These results find exploitable instances of enhanced chemosensitivity of compound MOA's for selected defective genes. Collectively these findings will advance the interpretation of pre-clinical screening data as well as contribute towards the goals of cancer drug discovery, development decision making, and explanation of drug mechanisms.
... The FAK pathway promotes cell motility and invasion by regulating matrix metalloproteinase (MMP) expression, focal adhesion turnover, and actin cytoskeletal dynamics [33,87]. Due to the potential role of FAK in cancer progression, a variety of inhibitors have been developed to target this molecule as a treatment for various cancers [33,88]. ...
Background
Extracellular vesicles (EVs) are small membrane particles that contribute to cancer progression and metastases by transporting biologically significant proteins and nucleic acids. They may also serve as biomarkers of various disease states or important therapeutic targets. Breast cancer EVs have the potential to change the behavior of other cells in their microenvironment. However, the proteomic content of EVs isolated from young women’s breast cancer patients and the mechanisms underlying the influence of EVs on tumor cell behavior have not yet been reported.
Methods
In our current translational studies, we compared the proteomic content of EVs isolated from invasive breast cancer cell lines and plasma samples from young women’s breast cancer (YWBC) patients and age-matched healthy donors using mass spectrometry. We analyzed the functionality of EVs in two dimensional tumor cell invasion assays and the gene expression changes in tumor cells after incubation with EVs.
Results
We found that treatment with EVs from both invasive breast cancer cell lines and plasma of YWBC patients altered the invasive properties of non-invasive breast cancer cells. Proteomics identified differences between EVs from YWBC patients and healthy donors that correlated with their altered function. Further, we identified gene expression changes in non-invasive breast cancer cells after treatment with EVs that implicate the Focal Adhesion Kinase (FAK) signaling pathway as a potential targetable pathway affected by breast cancer-derived EVs.
Conclusions
Our results suggest that the proteome of EVs from breast cancer patients reflects their functionality in tumor motility assays and may help elucidate the role of EVs in breast cancer progression.
... PTK2 (FAK), a protein tyrosine kinase in the RTK pathway, is an important mediator within the cell migration process, as well as in cell motility, survival and proliferation through kinase-dependent and -independent mechanisms [43]. Because of the involvement of PTK2(FAK) in many cancers, drugs that inhibit FAK are being sought and evaluated [44]. A screen to identify mechanisms of bleomycin resistance identified Sky1, PTK2 and Agp2 as determinants of chemosensitivity [45]. ...
A joint analysis of NCI60 small molecule screening data, their genetically defective genes and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-organizing-maps (SOMs) are used to organize the chemosensitivity data. Student’s t-tests are used to identify SOM clusters with chemosensitivity for tumor cells harboring genetically defective genes. Fisher’s exact tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. This analysis may contribute towards the goals of cancer drug discovery, development decision making, and explanation of mechanisms.
... In addition, we also assayed the expression of FAK, which is a cytoplasmic non-receptor tyrosine kinase that enables activation by growth factor receptors or integrins in various types of human cancers. It is a critical regulator in promoting cancer proliferation (Bullard Dunn et al., 2010;Tai et al., 2015). While from the results, the characteristics of PAD-CF scaffold seems to have no effect on the expression of FAK. ...
Neuroregenerative medicine has witnessed impressive technological breakthroughs in recent years, but the currently available scaffold materials still have limitations regarding the development of effective treatment strategies for neurological diseases. Electrically conductive micropatterned materials have gained popularity in recent years due to their significant effects on neural stem cell fate. Polydopamine (PDA)—modified materials can also enhance the differentiation of neurons. In this work, we show that PDA-modified carbon microfiber skeleton composites have the appropriate conductivity, three-dimensional structure, and microenvironment regulation that are crucial for the growth of neural stem cells. The design we present is low-cost and easy to make and shows great promise for studying the growth and development of mouse neural stem cells. Our results show that the PDA-mediated formation of electrically conductive and viscous nanofiber webs promoted the adhesion, organization, and intercellular coupling of neural stem cells relative to the control group. PDA induced massive proliferation of neural stem cells and promoted the expression of Ki-67. Together, our results suggest that the composite material can be used as a multifunctional neural scaffold for clinical treatment and in vitro research by improving the structure, conductivity, and mechanical integrity of the regenerated tissues.
... In addition to irradiation, we investigated the influence of an additional inhibition of FAK with the inhibitor PF-573, 228. This inhibitor inhibits phosphorylation and thus activation of FAK and its downstream effector paxillin and thus influences migration and adhesion [29][30][31][32][33]. Our data show an increase in the adhesion of tumor cells to the endothelial cells after irradiation, which correlates with an upregulation of adhesion proteins. ...
Background
Radiotherapy is administered in more than 60% of all solid tumors. Most patients are cured but a significant number develops local recurrences or distant metastases. The question arises if irradiation might influence the metastatic process. In the present study we examined whether the adhesion of glioblastoma or breast cancer cells to endothelial cells, an important step in metastasis, is affected by photon irradiation.
Methods
U-87 MG, U-373 MG and MDA-MB-231 cancer cells as well as primary human endothelial cells were irradiated with 0, 2, 4, or 8 Gy photons at a dose rate of 5 Gy/min. The adhesion of cancer cells to endothelial cells was tested either with the Vybrant based assay via fluorescent labelling or with an ibidi pump system able to mimic the physiological blood flow in vitro. In addition, the impact of FAK (focal adhesion kinase) inhibitor PF-573, 228 on the adhesion of non-irradiated and irradiated tumor cells was analyzed. Adhesion related and regulated proteins were analyzed by Western blotting.
Results
The cellular adhesion was increased after irradiation regardless of which cell type was irradiated. The FAK-inhibitor was able to reduce the adhesion of non-irradiated cells but also the irradiation-induced increase in adhesion of tumor cells to endothelium. Adhesion related proteins were enhanced after irradiation with 4 Gy or 8 Gy in both cells types. The increased adhesion after irradiation is accompanied by the phosphorylation of src (Y416), FAK (Y397) and increased expression of paxillin.
Conclusion
Irradiation with photons in therapeutic doses is able to enhance the interaction between tumor cells and endothelial cells and by that might influence important steps of the metastatic process.
... Despite the modest OS benefit achieved by adding bevacizumab to standard cisplatin plus pemetrexed chemotherapy [2], no other molecularly targeted drugs could so far enter the clinical practice for this fatal malignancy. Focal adhesion kinase (FAK), also known as protein tyrosine kinase 2 (PTK2), is a ubiquitously expressed 125-kDa non-receptor tyrosine kinase which consists of three distinct domains: a central catalytic domain, a C-terminal FAT domain, and an N-terminal FERM domain [3,4]. FAK is located in the cytosol, where it is particularly prominent in focal adhesions that interact with different extracellular matrix components [5]. ...
... FAK is located in the cytosol, where it is particularly prominent in focal adhesions that interact with different extracellular matrix components [5]. Accordingly, during homeostatic conditions, FAK activation mainly relies on signals from integrins and growth factor receptors, leading to autophosphorylation of the Y397 site in the N-terminal domain [3,4,[6][7][8]. FAK overexpression has been preferentially linked to a more aggressive tumor behavior, particularly by promoting tumor cell proliferation, survival, motility, invasion, stem cell renewal, angiogenesis, and metastasis [4,6,7,[9][10][11]. In this context, there is emerging evidence for a functional role of FAK gene amplification and protein overexpression during tumor progression in different tumor types including lung, breast, colorectal, thyroid, kidney, and pancreatic cancers as well as astrocytoma and osteosarcoma [10,[12][13][14]. ...
... Recognition of the crucial role of FAK in the aforementioned tumor promoting functions prompted the development of FAK small molecule inhibitors and their application for cancer therapy [3,6,9,14]. Early preclinical data provided a clear scientific rationale for the anti-tumorigenic effects mediated by FAK inhibitors, though concerns were raised about their potential toxicity via interacting with ATP binding sites on other tyrosine kinases [3]. ...
No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC50 values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC50 exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM.
Key messages
• Response to FAK inhibition in MPM is independent of NF2 expression or histotype.
• FAK inhibition strongly interfered with MPM spheroid formation.
• BI 853520 has been shown to exert anti-tumor effect in MPM.
