Automated FRET quantification shows distinct subcellular ERK activation kinetics in response to graded EGFR signaling in Drosophila.

Threshold responses to an activity gradient allow a single signaling pathway to yield multiple outcomes. Extracellular signal-regulated kinase (ERK) is one such signal, which couples receptor tyrosine kinase signaling with multiple cellular responses in various developmental processes. Recent advances in the development of fluorescent biosensors for live imaging have enabled the signaling activities accompanying embryonic development to be monitored in real time. Here, we used an automated computational program to quantify the signals of a fluorescence resonance energy transfer (FRET) reporter for activated ERK, and we used this system to monitor the spatio-temporal dynamics of ERK during neuroectoderm patterning in Drosophila embryos. We found that the cytoplasmic and nuclear ERK activity gradients show distinct kinetics in response to epidermal growth factor receptor activation. The ERK activation patterns implied that the cytoplasmic ERK activity is modulated into a threshold response in the nucleus.

STAT Signaling in Glioma Cells.

STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.

Targeting IGF1R pathway in cancer with microRNAs: How close are we?

Cancer of the head and neck are the most common cancers in India and account for 30% of all cancers. At molecular level, it could be attributed to the overexpression of growth factors like IGF1-R, EGFR, VEGF-R and deregulation of cell cycle regulators and tumor suppressors. IGF1-R is an emerging target in head and neck cancer treatment, because of its reported role in tumor development, progression and metastasis. IGF1R targeted agents are in advanced stages of clinical development. Nevertheless, these agents suffer from several disadvantages including acquired resistance and toxic side effects. Hence there is a need for developing newer agents targeting not only the receptor but also its downstream signaling. miRNAs are considered as master regulators of gene expression of multiple genes and has been widely reported to be a promising therapeutic strategy. This review discusses the present status of research in both these arenas and emphasizes the role of miRNA as a promising agent for biologic therapy.

The NG2 Proteoglycan in Pericyte Biology.

Studies of pericytes have been retarded by the lack of appropriate markers for identification of these perivascular mural cells. Use of antibodies against the NG2 proteoglycan as a pericyte marker has greatly facilitated recent studies of pericytes, emphasizing the intimate spatial relationship between pericytes and endothelial cells, allowing more accurate quantification of pericyte/endothelial cell ratios in different vascular beds, and revealing the participation of pericytes throughout all stages of blood vessel formation. The functional importance of NG2 in pericyte biology has been established via NG2 knockdown (in vitro) and knockout (in vivo) strategies that reveal significant deficits in blood vessel formation when NG2 is absent from pericytes. NG2 influences pericyte proliferation and motility by acting as an auxiliary receptor that enhances signaling through integrins and receptor tyrosine kinase growth factor receptors. By acting in a trans orientation, NG2 also activates integrin signaling in closely apposed endothelial cells, leading to enhanced maturation and formation of endothelial cell junctions. NG2 null mice exhibit reduced growth of both mammary and brain tumors that can be traced to deficits in tumor vascularization. Use of Cre-Lox technology to produce pericyte-specific NG2 null mice has revealed specific deficits in tumor vessels that include decreased pericyte ensheathment of endothelial cells, diminished assembly of the vascular basement membrane, reduced vessel patency, and increased vessel leakiness. Interestingly, myeloid-specific NG2 null mice exhibit even larger deficits in tumor vascularization, leading to correspondingly slower tumor growth. Myeloid-specific NG2 null mice are deficient in their ability to recruit macrophages to tumors and other sites of inflammation. This absence of macrophages deprives pericytes of a signal that is crucial for their ability to interact with endothelial cells. The interplay between pericytes, endothelial cells, and macrophages promises to be an extremely fertile area of future study.

M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7.

Determination of signaling pathways that regulate beta-cell replication is critical for beta-cell therapy. Here, we show that blocking pancreatic macrophage infiltration after pancreatic duct ligation (PDL) completely inhibits beta-cell proliferation. The TGFß superfamily signaling inhibitor SMAD7 was significantly up-regulated in beta cells after PDL. Beta cells failed to proliferate in response to PDL in beta-cell-specific SMAD7 mutant mice. Forced expression of SMAD7 in beta cells by itself was sufficient to promote beta-cell proliferation in vivo. M2, rather than M1 macrophages, seem to be the inducers of SMAD7-mediated beta-cell proliferation. M2 macrophages not only release TGFß1 to directly induce up-regulation of SMAD7 in beta cells but also release EGF to activate EGF receptor signaling that inhibits TGFß1-activated SMAD2 nuclear translocation, resulting in TGFß signaling inhibition. SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2, and by inducing nuclear exclusion of p27. Our study thus reveals a molecular pathway to potentially increase beta-cell mass through enhanced SMAD7 activity induced by extracellular stimuli.

Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer.

Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain. Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy. In the current review, we describe recent advances in anti-EGFR therapy and discuss new treatment strategies to target downstream RAS-MAPK signaling in mCRC.

Membrane rafts as a novel target in cancer therapy.

Membrane rafts are distinct plasma membrane microdomains that are enriched in sphingolipids and cholesterol. They organize receptors and their downstream molecules and regulate a number of intracellular signaling pathways. This review presents information on the dependence of several growth factor receptor signaling pathways on membrane rafts. It also discusses the involvement of rafts in the regulation of differentiation, apoptosis and cell migration connected with invasiveness and metastasis. Examples of known synthetic and naturally occurring substances that are known to affect lateral membrane organization in tumor cell growth are discussed as potential or actual therapeutics.

Emerging role of rhomboid family proteins in mammalian biology and disease.

From proteases that cleave peptide bonds in the plane of the membrane, rhomboids have evolved into a heterogeneous superfamily with a wide range of different mechanistic properties. In mammals 14 family members have been annotated based on a shared conserved membrane-integral rhomboid core domain, including intramembrane serine proteases and diverse proteolytically inactive homologues. While the function of rhomboid proteases is the proteolytic release of membrane-tethered factors, rhomboid pseudoproteases including iRhoms and derlins interact with their clients without cleaving them. It has become evident that specific recognition of membrane protein substrates and clients by the rhomboid fold reflects a spectrum of cellular functions ranging from growth factor activation, trafficking control to membrane protein degradation. This review summarizes recent progress on rhomboid family proteins in the mammalian secretory pathway and raises the question whether they can be seen as new drug targets for inflammatory diseases and cancer. This article is part of a special issue entitled: Intramembrane Proteases.

3D organoid cultivation improves the maturation and functional differentiation of cholangiocytes from human pluripotent stem cells.

Idiopathic cholangiopathies are diseases that affect cholangiocytes, and they have unknown etiologies. Currently, orthotopic liver transplantation is the only treatment available for end-stage liver disease. Limited access to the bile duct makes it difficult to model cholangiocyte diseases. In this study, by mimicking the embryonic development of cholangiocytes and using a robust, feeder- and serum-free protocol, we first demonstrate the generation of unique functional 3D organoids consisting of small and large cholangiocytes derived from human pluripotent stem cells (PSCs), as opposed to traditional 2D culture systems. At day 28 of differentiation, the human PSC-derived cholangiocytes expressed markers of mature cholangiocytes, such as CK7, CK19, and cystic fibrosis transmembrane conductance regulator (CFTR). Compared with the 2D culture system-generated cholangiocytes, the 3D cholangiocyte organoids (COs) showed higher expression of the region-specific markers of intrahepatic cholangiocytes YAP1 and JAG1 and extrahepatic cholangiocytes AQP1 and MUC1. Furthermore, the COs had small-large tube-like structures and functional assays revealed that they exhibited characteristics of mature cholangiocytes, such as multidrug resistance protein 1 transporter function and CFTR channel activity. In addition to the extracellular matrix supports, the epidermal growth factor receptor (EGFR)-mediated signaling regulation might be involved in this cholangiocyte maturation and differentiation. These results indicated the successful generation of intrahepatic and extrahepatic cholangiocytes by using our 3D organoid protocol. The results highlight the advantages of our 3D culture system over the 2D culture system in promoting the functional differentiation and maturation of cholangiocytes. In summary, in advance of the previous works, our study provides a possible concept of small-large cholangiocyte transdifferentiation of human PSCs under cost-effective 3D culture conditions. The study findings have implications for the development of effective cell-based therapy using COs for patients with cholangiopathies.

TWEAK increases angiogenesis to promote diabetic skin wound healing by regulating Fn14/EGFR signaling.

OBJECTIVE: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of tumor necrosis factor superfamily, can bind to fibroblast growth factor-inducible 14 (Fn14) receptor and stimulate angiogenesis. The interaction between epidermal growth factor receptor (EGFR) and endothelial growth factor (EGF) leads to EGFR signal transduction and promotes angiogenesis. The objective of this study was to explore whether TWEAK participated in the diabetic skin wound healing by regulating Fn14/EGFR signaling. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with 35 mmol/L d-glucose and classified into the Control Group, High Glucose (HG) Group and HG + TWEAK Group. Then, the TWEAK expression and the proliferation, migration and tubule formation of HUVECs were detected, respectively. In vivo experiment, the diabetic model was established by injecting streptozotocin (STZ, 50 mg/kg) into male BALB/c mice. On the back of successfully modeled diabetic mice, a full-thickness skin wound of 6 mm diameter was formed. Then, the mice were randomly assigned into three groups: Blank Group, Phosphate Buffer Saline (PBS) Group, and TWEAK Group. Subsequently, expression levels of TWEAK, Fn14, EGFR and vascular endothelial growth factor (VEGF)-A were measured, and the CD31 expression in the wounded skin tissue of mice was checked by immunohistochemistry staining. RESULTS: The expression level of TWEAK in HUVECs of HG Group decreased significantly, as well as the viability, migration, and tubule formation of cells. After over-expression of TWEAK, the cell viability, migration, and tubule formation abilities of HUVECs recovered remarkably. In vivo, the wound healing rate of diabetic mice was raised, the neovascularization was increased, and the CD31 expression in the wounded tissue was obviously upregulated after injection with recombinant TWEAK antibody. CONCLUSION: TWEAK stimulates angiogenesis and accelerates the wound healing of diabetic skin by regulating Fn14/EGFR signaling.

[Retracted] Filamin A regulates EGFR/ERK/Akt signaling and affects colorectal cancer cell growth and migration.

Following the publication of this article, an interested reader drew to the authors' attention that various panels in the scratch-wound assays shown in Fig. 1C appeared to contain overlapping sections, such that the data may have been derived from a more limited selection of original sources where the data were intended to show the data from discrete experiments. Furthermore, the results shown in the Kaplan-Meier overall survival analysis plots in Fig. 4C appeared to be inconsistent with the date of publication of this article. Independently, the Editorial Office also investigated the issues of concern in this article, and although the authors attenpted to explain these issues and requested the publication of a corrigendum, the Editor of Molecular Medicine Reports has declined this request and determined that this article should be retracted from the journal on the basis of an overall lack of confidence in the presented data. Upon receiving this decision from the Editor, the authors were not in agreement that the article should be retracted. The Editor apologizes to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 20: 3671-3678, 2019; DOI: 10.3892/mmr.2019.10622].

Dacomitinib improves chemosensitivity of cisplatin-resistant human ovarian cancer cells.

Drug resistance hinders effectiveness of human ovarian cancer (OC) therapies, such as cisplatin or paclitaxel therapy. Although dacomitinib, a novel anticancer agent is used against multiple types of cancers, such as non-small cell lung cancer, head and neck cancer, few studies report its effectiveness in drug-resistant human OC cells. In the present study, would healing, microplate spectrophotometer analysis, flow cytometry analysis, western blotting and Gene Expression Omnibus (GEO) analysis were used to detect the synergistic effect of dacomitinib and cisplatin in human OC SKOV-3 or OV-4 cells. Co-administration of dacomitinib and cisplatin significantly reduced viability and promoted cell apoptosis of drug resistant OC cells. In addition, dacomitinib increased Cadherin 1 (CDH1) levels and decreased P-glycoprotein (P-GP) levels in cisplatin-resistant OC cells. In addition, GEO analysis demonstrated that dacomitinib inhibited the epidermal growth factor receptor (EGFR) signaling pathway. In summary, dacomitinib improves chemosensitivity of cisplatin in human OC by regulating CDH1 and P-GP protein levels and inhibiting the EGFR signaling pathway.

HECTD1 regulates the expression of SNAIL: Implications for epithelial­mesenchymal transition.

As a transcription factor, SNAIL plays a crucial role in embryonic development and cancer progression by mediating epithelial­mesenchymal transition (EMT); however, post­translational modifications, such as ubiquitination, which control the degradation of SNAIL have been observed to affect its functional role in EMT. In a previous study by the authors, it was demonstrated that the HECT domain E3 ubiquitin ligase 1 (HECTD1) regulated the dynamic nature of adhesive structures. In the present study, HECTD1 was observed to interact with SNAIL and regulate its stability through ubiquitination, and the knockdown of HECTD1 increased the expression levels of SNAIL. HECTD1 was discovered to contain putative nuclear localization and export signals that facilitated its translocation between the cytoplasm and nucleus, a process regulated by epidermal growth factor (EGF). Treatment with leptomycin B resulted in the nuclear retention of HECTD1, which was associated with the loss of SNAIL expression. The knockdown of HECTD1 in HeLa cells increased cell migration and induced a mesenchymal phenotype, in addition to demonstrating sustained EGF signaling, which was observed through increased phosphorylated ERK expression levels. Under hypoxic conditions, HECTD1 expression levels were decreased by microRNA (miRNA or miR)­210. Upon the observation of genetic abnormalities in the HECTD1 gene in cervical cancer specimens, it was observed that the decreased expression levels of HECTD1 were significantly associated with a poor patient survival. Thus, it was hypothesized that HECTD1 may regulate EMT through the hypoxia/hypoxia inducible factor 1α/miR­210/HECTD1/SNAIL signaling pathway and the EGF/EGF receptor/HECTD1/ERK/SNAIL signaling pathway in cervical cancer. On the whole, the data of the present study indicated that HECTD1 serves as an E3 ubiquitin ligase to mediate the stability of SNAIL proteins.

STAU1 selectively regulates the expression of inflammatory and immune response genes and alternative splicing of the nerve growth factor receptor signaling pathway.

Double­stranded RNA­binding protein Staufen homolog 1 (STAU1) is a highly conserved multifunctional double­stranded RNA­binding protein, and is a key factor in neuronal differentiation. RNA sequencing was used to analyze the overall transcriptional levels of the upregulated cells by STAU1 and control cells, and select alternative splicing (AS). It was determined that the high expression of STAU1 led to changes in the expression levels of a variety of inflammatory and immune response genes, including IFIT2, IFIT3, OASL, and CCL2. Furthermore, STAU1 was revealed to exert a significant regulatory effect on the AS of genes related to the 'nerve growth factor receptor signaling pathway'. This is of significant importance for neuronal survival, differentiation, growth, post­damage repair, and regeneration. In conclusion, overexpression of STAU1 was associated with immune response and regulated AS of pathways related to neuronal growth and repair. In the present study, the whole transcriptome of STAU1 expression was first analyzed, which laid a foundation for further understanding the key functions of STAU1.

Shenkang injection, a modern preparation of Chinese patent medicine, diminishes tubulointerstitial fibrosis in obstructive nephropathy via targeting pericyte-myofibroblast transition.

Shenkang injection (SKI), a modern preparation of Chinese patent medicine, has been widely applied to clinical therapy in the chronic renal failure patients. However, it remains elusive whether SKI can ameliorate tubulointerstitial fibrosis (TIF) in vivo. Recently, pericyte-myofibroblast transition (PMT) plays an important role in the pathogenesis of TIF in obstructive nephropathy (ON). This report thus aims to demonstrate the therapeutic mechanisms of the dose-effects of SKI on TIF by targeting PMT and its signaling activation, compared with imatinib. All rats were divided into 5 groups, the sham-operated group, the vehicle-intervened group, the high dose of SKI-treated group, the low dose of SKI-treated group and the imatinib-treated group. The ON model rats were induced by unilateral ureteral obstruction (UUO), and administered with either the different doses of SKI or imatinib before and after modeling and for a period of 4 weeks. The changes before and after drugs intervention in TIF and PMT markers, and in platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways activation in the kidneys were analyzed, respectively. As a result, PMT trigger was persistently accompanied with TIF exasperation in the obstructed kidneys after UUO, and that SKI definitely targeted PMT and significantly diminished TIF in vivo. In addition, the high dose of SKI, superior to imatinib, specifically blocked PMT through inhibiting the activation of PDGFR and VEGFR signaling in the kidneys of the UUO model rats. Overall, these findings may further suggest that targeting PMT can provide new strategies for ON treatment.

Desmoglein 3 gene mediates epidermal growth factor/epidermal growth factor receptor signaling pathway involved in inflammatory response and immune function of anaphylactic rhinitis.

OBJECTIVE: To investigate the effects of desmoglein 3 (DSG3) gene mediating epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling pathway on inflammatory response and immune function of anaphylactic rhinitis (AR). METHODS: Ten of the seventy male BALB/c mice were randomly selected as the normal control group, and the remaining 60 were used to construct the AR mice model. AR model mice were divided into 6 groups: model group (instilled with 5 µL saline), empty vector group (instilled with 5 µL of liposome and empty vector mixture), siRNA-DSG3 group (instilled with 5 µL of liposome and siRNA-DSG3 carrier mixture), AG1478 group (instilled with 5 µL of EGF/EGFR inhibitor AG1478), siRNA-DSG3+AG1478 group (instilled with 5 µL of liposome and siRNA-DSG3 carrier and EGF/EGFR inhibitor AG1478 mixture) and oe-DSG3 group, 10 in each group. After taking serum, each group of mice was sacrificed to get nasal mucosa tissues. HE staining was used to observe the pathological changes of nasal mucosa tissues in each group. The expression levels of DSG3, EGF and EGFR in nasal mucosa tissues of mice in each group were detected by qRT-PCR and western blot methods respectively. TUNEL staining was used to observe the apoptosis of nasal mucosa cells in mice. The expression of IgE, INF-γ, TNF-α, IL-2, IL-4 and IL-6 in serum of mice was determined by ELISA method. The immune adhesion function of red blood cells was detected by complement sensitization yeast hemagglutination method. RESULTS: All the mice with AR showed different degrees of nasal mucosa injury and inflammatory cell infiltration, and silencing DSG3 or inhibiting the activity of EGF signaling pathway could alleviate the nasal mucosa injury. Compared with control group, the INF-γ and IL-2 levels of serum in AR model mice were significantly decreased; IgE, TNF-α, IL-4 and IL-6 levels were significantly increased (all P < 0.05); the mRNA expression levels and protein levels of DSG3, EGF and EGFR were significantly increased (all P < 0.05); C3b receptor rosette rate and Ic rosette rate were significantly decreased (all P < 0.05). Detected by ELISA method, the expression levels of IgE, TNF-α, IL-4 and IL-6 were increased, while the expression levels of INF-γ and IL-2 were decreased after DSG3 silencing or using AG1478. Detected by qRT-PCR and western blot methods, the expression of DSG3, EGF and EGFR did decrease after DSG3 silencing. There was no significant difference in the EGF and EGFR expression between DSG3 silencing and using AG1478, and the expression decreased even more under the double effect. The mRNA and protein expression levels of DSG3, EGF and EGFR in the nasal mucosa tissues of mice with overexpression of DSG3 plasmid were significantly higher than those of normal mice (all P < 0.05). CONCLUSION: Silencing DSG3 gene can inhibit the activation of EGF signaling pathway, alleviate the inflammation of AR nasal mucosa, and enhance red blood cells immune adherence function.

Lentivirus-mediated silencing of HOTAIR lncRNA restores gefitinib sensitivity by activating Bax/Caspase-3 and suppressing TGF-α/EGFR signaling in lung adenocarcinoma.

Secondary resistance is a major limitation in the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of lung cancer. Previous studies have shown that expression of the long non-coding RNA HOX transcript antisense RNA (HOTAIR) is upregulated in lung cancer, which is correlated with metastasis and poor prognosis. However, the precise role of HOTAIR and its effects on gefitinib resistance in human lung adenocarcinoma are not known. To address this issue, in the present study we established a gefitinib-resistant (R)PC-9 human lung adenocarcinoma cell line and examined cell viability with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. We found that gefitinib concentrations <10 µM inhibited the viability of PC-9 but not RPC-9 cells in a dose-dependent manner. Lentivirus-mediated HOTAIR RNA interference induced cell apoptosis and S-phase arrest, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and flow cytometry. Consistent with these observations, HOTAIR suppression was associated with tumor shrinkage and restoration of gefitinib sensitivity in RPC-9 xenograft mice. Immunohistochemical analyses and western blot revealed that HOTAIR silencing resulted in the upregulation of B cell lymphoma 2-associated X protein (Bax), Caspase-3 and transforming growth factor α (TGF-α) and downregulation of EGFR and B cell lymphoma 2 (Bcl-2) levels. These results indicate that HOTAIR normally prevents the activation of Bax/Caspase-3 while inducing TGF-α/EGFR signaling. Thus, targeting HOTAIR may be a novel therapeutic strategy for treating gefitinib-resistant lung adenocarcinoma.

Role of Annexin A2 in the EGF-induced epithelial-mesenchymal transition in human CaSki cells.

The epidermal growth factor receptor (EGF-R) signaling pathway is thought to have an important role in the development and progression of several carcinomas, as it is associated with cell proliferation, differentiation and migration. Activation of EGF-R signaling regulates epithelial-mesenchymal transition (EMT)-associated invasion and migration in normal and malignant epithelial cells. However, the specific mechanisms have not yet been fully elucidated. The present study utilized wound healing assays, western blotting, flow cytometry and MTT assays to demonstrate that Annexin A2 (ANXA2) is a key regulatory factor in EGF-induced EMT in CaSki cervical cancer cells. Moreover, the increased expression levels of ANXA2 promoted cell viability and migration in human CaSki cells. It was also found that silencing ANXA2 partially reverses EGF-induced EMT and inhibits cell viability and migration in CaSki cells. These findings suggest that ANXA2 is a key regulator of EGF-induced EMT in CaSki cervical cancer cells.

TRPV1: Turning up the heat on intestinal tumorigenesis.

TRP channels are associated with the development and progression of cancer but their precise molecular roles in these processes are unclear. Recently, we showed that the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) ion channel is part of a negative feedback loop downstream of epidermal growth factor receptor signaling that suppresses intestinal tumorigenesis.

Crenolanib, a PDGFR inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo.

Platelet-derived growth factor (PDGF) and its receptors (PDGFR), including PDGFRα and PDGFRß, play important roles in tumorigenesis, tumor progression, and the regulation of stromal cell function. Constitutive activation of PDGFR signaling, gene rearrangement, and activating mutations of PDGFR have been identified in various types of human tumors and malignancies. PDGFRα and PDGFRß belong to the family of type III receptor tyrosine kinases and, upon stimulation, activate downstream signaling cascades. Crenolanib is a specific tyrosine kinase inhibitor that targets and inhibits the kinase activity of PDGFR and the FMS-related tyrosine kinase 3. Its clinical efficacy in several human tumors is currently under investigation in Phase II clinical trials. In this study, we examined the potential role of crenolanib in the treatment of non-small-cell lung cancer (NSCLC). Using A549 cells as a model system, we have shown that crenolanib is capable of suppressing proliferation and inducing apoptosis in a dose-dependent manner. Crenolanib-treated cells have reduced migratory activity in response to inducers of chemotaxis. Furthermore, the in vivo antitumor activity of crenolanib was confirmed in an NSCLC xenograft tumor model. Injection of crenolanib significantly inhibited the growth of tumor mass by inducing apoptosis in tumor cells. Our results provide strong evidence supporting the use of crenolanib as a potential therapeutic agent in treating NSCLC. This work sets a foundation for further development of targeted and personalized therapeutics for lung cancer.