• Drug Discovery
• Inhibitor
• Protein-protein Interaction
• Split Intein
• Tri-part Nanoluciferase

• Inteins
• Luciferases/genetics
• Luciferases/metabolism
• Protein Interaction Mapping/methods
• Humans
• High-Throughput Screening Assays/methods
• Drug Discovery/methods
• Protein Splicing
• Luminescent Measurements/methods
• Protein Binding

• #OGI-117 Ontario Genomics (OG)
• #OGI-159 Ontario Genomics (OG)
• #OGI-120 Ontario Genomics (OG)
• #507942 FACIT

• 5-Lipoxygenase
• Inflammation
• Leukotrienes
• Michael acceptors
• Tyrphostin

• Humans
• Arachidonate 5-Lipoxygenase/metabolism
• Lipoxygenase Inhibitors/pharmacology
• Tyrphostins/pharmacology
• Cyanoacrylates/pharmacology
• Cyanoacrylates/chemistry
• Neutrophils/metabolism
• Neutrophils/drug effects

• TRABITA LOEWE Project by the Hessian Ministry of Higher Education, Research, Science and Arts
• SFB 1039 Deutsche Forschungsgemeinschaft

• Absolute protein binding free energy
• Epidermal growth factor receptor (EGFR)
• Imidazole[1,5-a]pyridines
• Steered molecular dynamics simulation
• Tyrosine kinase inhibitors (TKI)
• Umbrella sampling molecular dynamics simulation

• Molecular Dynamics Simulation
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/chemistry
• ErbB Receptors/metabolism
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Imidazoles/chemistry
• Imidazoles/pharmacology
• Pyridines/chemistry
• Pyridines/pharmacology
• Humans
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Erlotinib Hydrochloride/chemistry
• Erlotinib Hydrochloride/pharmacology
• Drug Design
• Molecular Docking Simulation
• Protein Binding
• Tyrosine Kinase Inhibitors

• VINIF.2021.DA00203. Quỹ Đổi mới sáng tạo Vingroup

• VEGF
• VEGFR
• angiogenesis
• anti-angiogenic
• inhibitors

• CADD
• LBDD
• SBDD
• kinase
• small molecule kinase inhibitors

Breast cancer is one of the most common malignancies and the leading cause of cancer-related death in women. HER2 overexpression is a factor for poor prognosis in breast cancer, and anti-HER2 therapy improves survival in these patients. A dual-targeted combination of pertuzumab and trastuzumab, alongside cytotoxic chemotherapy, constitutes the primary treatment option for individuals with early-stage, HER2-positive breast cancer. Antibody-drug conjugate (ADC) and tyrosine kinase inhibitors (TKI) also increase the prognosis for patients with metastatic breast cancer. However, resistance to targeted therapy eventually occurs. Therefore, it is critical to investigate how HER2-positive breast cancer is resistant to targeted therapy and to develop novel drugs or strategies to overcome the resistance simultaneously. This review aims to provide a comprehensive discussion of the HER2-targeted agents currently in clinical practice, the molecular mechanisms of resistance to these drugs, and the potential strategies for overcoming resistance.

• NK cell
• T-cell
• bispecific antibody
• cancer
• immune-cell engager
• therapeutic target

• Humans
• Immunotherapy
• Neoplasms/drug therapy
• United States

• NRF-2019M3E5D5065844, NRF-2020M3A9I2107093 Bio & Medical Technology Development Program of the National Research Foundation

Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC₅₀ value of 0.9 µM (IMT, CC₅₀ = 0.08 µM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT.

Human mesenchymal stem cells (MSCs) are emerging as a treatment for atopic dermatitis (AD), a chronic inflammatory skin disorder that affects a large number of people across the world. Treatment of AD using human umbilical cord blood-derived MSCs (hUCB-MSCs) has recently been studied. However, the mechanism underlying their effect needs to be studied continuously. Thus, the objective of this study was to investigate the immunomodulatory effect of epidermal growth factor (EGF) secreted by hUCB-MSCs on AD.

To explore the mechanism involved in the therapeutic effect of MSCs for AD, a secretome array was performed using culture medium of hUCB-MSCs. Among the list of genes common for epithelium development and skin diseases, we focused on the function of EGF. To elucidate the effect of EGF secreted by hUCB-MSCs, EGF was downregulated in hUCB-MSCs using EGF-targeting small interfering RNA. These cells were then co-cultured with keratinocytes, Th2 cells, and mast cells. Depletion of EGF disrupted immunomodulatory effects of hUCB-MSCs on these AD-related inflammatory cells. In a Dermatophagoides farinae-induced AD mouse model, subcutaneous injection of hUCB-MSCs ameliorated gross scoring, histopathologic damage, and mast cell infiltration. It also significantly reduced levels of inflammatory cytokines including interleukin (IL)-4, tumor necrosis factor (TNF)-α, thymus and activation-regulated chemokine (TARC), and IL-22, as well as IgE levels. These therapeutic effects were significantly attenuated at all evaluation points in mice injected with EGF-depleted hUCB-MSCs.

EGF secreted by hUCB-MSCs can improve AD by regulating inflammatory responses of keratinocytes, Th2 cells, and mast cells.

Gefitinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the epidermal growth factor receptor (EGFR), hampering cell growth and proliferation. Due to its action, gefitinib has been used in the treatment of cancers that present abnormally increased expression of EGFR. However, side effects from gefitinib therapy may occur, among which diarrhoea is most common, that can lead to interruption of the planned therapy in the more severe cases. The mechanisms underlying intestinal toxicity induced by gefitinib are not well understood. Therefore, this study aims at providing insight into these mechanisms based on transcriptomic responses induced in vitro. A 3D culture of healthy human colon and small intestine (SI) organoids was exposed to 0.1, 1, 10 and 30 µM of gefitinib, for a maximum of three days. These drug concentrations were selected using physiologically-based pharmacokinetic simulation considering patient dosing regimens. Samples were used for the analysis of viability and caspase 3/7 activation, image-based analysis of structural changes, as well as RNA isolation and sequencing via high-throughput techniques. Differential gene expression analysis showed that gefitinib perturbed signal transduction pathways, apoptosis, cell cycle, FOXO-mediated transcription, p53 signalling pathway, and metabolic pathways. Remarkably, opposite expression patterns of genes associated with metabolism of lipids and cholesterol biosynthesis were observed in colon versus SI organoids in response to gefitinib. These differences in the organoids’ responses could be linked to increased activated protein kinase (AMPK) activity in colon, which can influence the sensitivity of the colon to the drug. Therefore, this study sheds light on how gefitinib induces toxicity in intestinal organoids and provides an avenue towards the development of a potential tool for drug screening and development.

• Aged
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Cycle/drug effects
• Cell Proliferation/drug effects
• Drug Resistance, Neoplasm/drug effects
• ErbB Receptors/metabolism
• Gefitinib/pharmacology
• Humans
• Intestines/drug effects
• Intestines/metabolism
• Male
• Organoids/drug effects
• Organoids/metabolism
• Quinazolines/pharmacology
• Signal Transduction/drug effects
• Transcriptome/genetics
• Tumor Suppressor Protein p53/metabolism

Amplification of ubiquitin E3 ligase Smurf1 promotes degradation of PTEN leading to hyperactivation of the Akt/mTORC1 pathway. However, inhibitors of this pathway have not hitherto yielded promising results in clinical studies because of strong drug resistance. Here, we investigated Smurf1 expression in various glioblastoma (GB) cell lines and patient tissues. The therapeutic efficacy of Smurf1 silencing and Torin1 treatment was assessed in GB cells and orthotopic mouse model. We found Smurf1 loss elevates PTEN levels that interrupt the epidermal growth factor receptor pathway activity. Cotreatment with Smurf1 silencing and mTORC1/C2 inhibitor Torin1 remarkably decreased phosphorylation of Akt, and mTORC1 downstream targets 4EBP1 and S6K resulting in synergistic inhibitory effects. Smurf1 knockdown in orthotopic GB mouse model impaired tumor growth and enhanced cytotoxicity of Torin1. Together, these findings suggest a rational combination of Smurf1 inhibition and Torin1 as a promising new avenue to circumvent PI3K/Akt pathway-driven tumor progression and drug resistance.

•

Smurf1 ubiquitylates and degrades PTEN, leading to upregulating oncogenic pathways

• Molecular biology
• Oncology

• anticancer compounds
• cytotoxicity
• fluorescence detection
• high-throughput
• lung cancer model
• phenotypic screening

• (phenylamino)pyrimidine-pyridine
• 1,2,3-triazole
• 1,3-dipolar cycloaddition
• chronic myeloid leukemia
• imatinib

• Hyperprogressive disease
• Immune checkpoint inhibitors
• Immunotherapy
• Renal cell carcinoma
• Targeted therapy

With the development of computer technology, screening cancer biomarkers based on public databases has become a common research method. Here, an eight-gene prognostic model, which could be used to judge the prognosis of patients with lung adenocarcinoma (LUAD), was developed through bioinformatics methods. This study firstly used several gene datasets from GEO database to mine differentially expressed genes (DEGs) in LUAD tissue and healthy tissue via joint analysis. Later, enrichment analysis for the DEGs was performed, and it was found that the DEGs were mainly activated in pathways involved in extracellular matrix, cell adhesion, and leukocyte migration. Afterward, a TCGA cohort was used to perform univariate Cox, least absolute shrinkage and selection operator method, and multivariate Cox regression analyses for the DEGs, and a prognostic model consisting of eight genes (GPX3, TCN1, ASPM, PCP4, CAV2, S100P, COL1A1, and SPOK2) was established. Receiver operation characteristic (ROC) curve was then used to substantiate the diagnostic efficacy of the prognostic model. The survival significance of signature genes was verified through the GEPIA database, and the results exhibited that the risk coefficients of the eight genes were basically congruous with the effects of these genes on the prognosis in the GEPIA database, which suggested that the results were accurate. Finally, combined with clinical characteristics of patients, the diagnostic independence of the prognostic model was further validated through univariate and multivariate regression, and the results indicated that the model had independent prognostic value. The overall finding of the study manifested that the eight-gene prognostic model is closely related to the prognosis of LUAD patients, and can be used as an independent prognostic indicator. Additionally, the prognostic model in this study can help doctors make a better diagnosis in treatment and ultimately benefit LUAD patients.

• TCGA
• biomarker
• gene signature
• lung adenocarcinoma
• prognosis

• 1,2,3-Triazole
• Anticancer
• Apoptosis
• Cell cycle
• EGFR
• Icotinib

In both normal and tumor tissues, receptor tyrosine kinases (RTKs) may be pleiotropically expressed. The RTKs not only regulate ordinary cellular processes, including proliferation, survival, adhesion, and migration, but also have a critical role in the development of many types of cancer. The Tyro3, Axl, and MerTK (TAM) family of RTKs (Tyro3, Axl, and MerTK) plays a pleiotropic role in phagocytosis, inflammation, and normal cellular processes. In this article, we highlight the cellular activities of TAM receptors and discuss their roles in cancer and immune cells. We also discuss cancer therapies that target TAM receptors. Further research is needed to elucidate the function of TAM receptors in immune cells toward the development of new targeted immunotherapies for cancer.

• Axl
• MerTK
• Tumor immune microenvironment
• Tyro3
• and MerTK receptors

• EGFR
• Quinazolines
• SAR
• TKIs

Here, to overcome many limitations accompanying current available methods to detect protein-protein interactions (PPIs), we develop a live cell method called Split Intein-Mediated Protein Ligation (SIMPL). In this approach, bait and prey proteins are respectively fused to an intein N-terminal fragment (IN) and C-terminal fragment (IC) derived from a re-engineered split intein GP41-1. The bait/prey binding reconstitutes the intein, which splices the bait and prey peptides into a single intact protein that can be detected by regular protein detection methods such as Western blot analysis and ELISA, serving as readouts of PPIs. The method is robust and can be applied not only in mammalian cell lines but in animal models such as C. elegans. SIMPL demonstrates high sensitivity and specificity, and enables exploration of PPIs in different cellular compartments and tracking of kinetic interactions. Additionally, we establish a SIMPL ELISA platform that enables high-throughput screening of PPIs and their inhibitors.

Protein-protein interactions are fundamental to the regulation of protein activity and cellular phyisology. Here the authors present Split Intein-Mediated Protein Ligation, which uses bait and prey proteins fused to intein fragments to generate single intact proteins upon interaction.

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

• ABC, adenosine triphosphate-binding cassette
• ABCB1, ABC transporter subfamily B member 1
• ABCG2
• ABCG2, ABC transporter subfamily G member 2
• AKT, protein kinase B
• ATP, adenosine triphosphate
• ATPase
• DDP, cisplatin
• DMEM, Dulbecco's modified Eagle's medium
• DMSO, dimethyl sulfoxide
• DOX, doxorubicin
• EGFR, epidermal growth factor receptor
• ERK, extracellular signal-regulated kinase
• FBS, fetal bovine serum
• FTC, fumitremorgin C
• GAPDH, glyceraldehyde 3-phosphate dehydrogenase
• IAAP, iodoarylazidoprazosin
• IC50, half maximal (50%) inhibitory concentration
• MDR, multidrug resistance
• MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazoliumbromide
• MX, mitoxantrone
• Multidrug resistance
• PBS, phosphate buffer saline
• PTK, protein tyrosine kinases
• Rho 123, rhodamine 123
• Rociletinib
• TKIs, tyrosine kinase inhibitors
• Tyrosine kinase inhibitor
• VCR, vincristine
• VRP, verapamil

The lumen of the fallopian tube (FT) is lined with columnar epithelium composed of secretory and ciliated cells, both of which are important for reproduction. However, the molecular mechanism regulating cell fate remains controversial. In this study, we established a primary culture system using porcine fallopian tube epithelial cells (FTECs) to study the differentiation mechanism. We found that estrogen promoted the differentiation of multi-ciliated cells (MCCs) through estrogen receptor β, following the reduction of DLL1, a ligand of Notch. Meanwhile, epidermal growth factor (EGF), a regulator of epithelial homeostasis and differentiation, suppressed ciliogenesis by the activation of Notch signaling. However, the estrogen pathway did not affect the activation of the EGF pathway. Taken together, the differentiation of MMCs in FT depends on the balance of EGF and estrogen signaling, either of which inhibits or stimulates the Notch signaling pathway respectively.

• DLL1
• ERβ
• differentiation
• high-grade serous ovarian cancer
• motile cilia

• Genistein
• Non-alcoholic fatty liver disease (NAFLD)
• Nonalcoholic steatohepatitis (NASH)
• Review
• Soy

• cancer
• immunotherapy
• targeted therapy
• tyrosine kinase
• tyrphostin

Protein tyrosine kinases (TKs) are a family of enzymes that catalyze the phosphorylation of proteins at tyrosine residues. TKs play key roles in controlling cell growth and many other functions by modulating the status of tyrosine phosphorylation of regulatory proteins critical for numerous cellular signaling pathways. Dysregulation of TKs caused by genetic abnormalities (mutation, amplification, fusion, etc.) results in uncontrolled cell growth, and ultimately leads to cancer. Thus, identification of dysregulated TK(s) in a specific cancer type and development of TK inhibitors (TKIs) that can potently block activity of the dysregulated TK establish the foundation of modern targeted cancer therapies. The 2018 Tang Prize in Biopharmaceutical Science was awarded to Tony Hunter as well as Brian Druker and John Mendelsohn for their great contributions in discovering oncogene src as a TK and developing small molecule TKIs or therapeutic monoclonal antibodies against receptor TK, respectively.

• 2018 Tang Prize
• Oncogene
• Targeted cancer therapy
• Tyrosine kinase inhibitor
• Tyrosine phosphorylation

• GTPase activity
• dynamin
• endocytosis
• inhibitor
• small molecules

• RNA
• enzyme inhibitor
• ribonuclease
• target identification

• drug safety
• pharmacodynamics
• pharmacovigilance

• anticancer agents
• boron
• drug design
• tyrosine kinases
• tyrphostins

• HMGA2
• anaplastic thyroid cancer
• epigenetics
• histone deacetylase inhibitors
• miRNAs
• poorly differentiated thyroid cancer
• sodium iodide symporter
• tyrosine kinase inhibitors

Neuroblastoma (NB) is one of the most common pediatric malignancies in children. Abnormal activation of receptor tyrosine kinases contributes to the pathological development of NB. Therefore, targeting tyrosine kinase receptors to cure NB is a promising strategy. Here, we report that a multi-targeted tyrosine kinase inhibitor ponatinib inhibited NB cell proliferation and induced NB cell apoptosis in a dose-dependent manner. In addition, ponatinib suppressed the colony formation ability of NB cells. Mechanistically, ponatinib effectively inhibited the FGFR1-activated signaling pathway. Ponatinib also enhanced the cytotoxic effects of doxorubicin on NB cells. Furthermore, ponatinib demonstrated anti-tumor efficacy in vivo by inhibiting tumor growth in an orthotopic xenograft NB mouse model. In summary, our results showed that ponatinib inhibited NB growth both in vitro and in vivo.

• FGFR1
• apoptosis
• chemoresistance
• neuroblastoma
• ponatinib

Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporter such as ABCB1, ABCC1, ABCG2 limited successful cancer chemotherapy. Unfortunately, no commercial available MDR modulator approved by FDA was used in clinic. Tyrosine kinase inhibitors (TKIs) have been administrated to fight against cancer for decades. Almost TKI was used alone in clinic. However, drug combinations acting synergistically to kill cancer cells have become increasingly important in cancer chemotherapy as an approach for the recurrent resistant disease. Here, we summarize the effect of TKIs on enhancing the efficacy of conventional chemotherapeutic drug in ABC transporter-mediated MDR cancer cells, which encourage to further discuss and study in clinic.

• ABC transporter
• Chemosensitizer
• Chemotherapy
• Multiple drug resistance
• Tyrosine kinase inhibitor

Tumor invasion through a basement membrane is one of the earliest steps in metastasis, and growth factors, such as Epidermal Growth Factor (EGF) and Hepatocyte Growth Factor (HGF), stimulate this process in a majority of solid tumors. Basement membrane breakdown is one of the hallmarks of invasion; therefore, tumor cells secrete a variety of proteases to aid in this process, including lysosomal proteases. Previous studies demonstrated that peripheral lysosome distribution coincides with the release of lysosomal cathepsins.

Immunofluorescence microscopy, western blot, and 2D and 3D cell culture techniques were performed to evaluate the effects of EGF on lysosome trafficking and cell motility and invasion.

EGF-mediated lysosome trafficking, protease secretion, and invasion is regulated by the activity of p38 mitogen activated protein kinase (MAPK) and sodium hydrogen exchangers (NHEs). Interestingly, EGF stimulates anterograde lysosome trafficking through a different mechanism than previously reported for HGF, suggesting that there are redundant signaling pathways that control lysosome positioning and trafficking in tumor cells.

These data suggest that EGF stimulation induces peripheral (anterograde) lysosome trafficking, which is critical for EGF-mediated invasion and protease release, through the activation of p38 MAPK and NHEs. Taken together, this report demonstrates that anterograde lysosome trafficking is necessary for EGF-mediated tumor invasion and begins to characterize the molecular mechanisms required for EGF-stimulated lysosome trafficking.

The online version of this article (10.1186/s12885-017-3660-3) contains supplementary material, which is available to authorized users.

• 3D culture
• EGF
• Invasion
• Lysosome
• NHE
• Signaling
• Trafficking
• p38

• Advanced thyroid cancer
• adverse events
• molecular targets
• targeted therapy
• tyrosine kinase inhibitors

• Abscisic acid
• Auxin
• Cell biology
• Cytokinins
• Inhibitors
• Plant hormones
• Strigolactones
• Transport

• Biological Transport
• Models, Biological
• Plant Growth Regulators/metabolism
• Plant Proteins/metabolism

• ABC transporters
• SLC transporters
• clinical trials
• drug resistance
• interindividual variability
• pharmacogenomics
• tyrosine kinase inhibitors

• AG-1478
• Solvatochromism
• Tyrosine kinase inhibitor
• UV–Vis spectroscopy

• Hydrogen Bonding
• Protein Kinase Inhibitors/chemistry
• Quinazolines/chemistry
• Solvents/chemistry
• Spectrometry, Fluorescence
• Spectrophotometry, Ultraviolet/methods
• Tyrphostins/chemistry

• Chromatographic bioanalysis
• Kinase inhibitor
• LC–MS/MS
• Oncology

ATP production requires the establishment of an electrochemical proton gradient across the inner mitochondrial membrane. Mitochondrial uncouplers dissipate this proton gradient and disrupt numerous cellular processes, including vesicular trafficking, mainly through energy depletion. Here we show that Endosidin9 (ES9), a novel mitochondrial uncoupler, is a potent inhibitor of clathrin-mediated endocytosis (CME) in different systems and that ES9 induces inhibition of CME not because of its effect on cellular ATP, but rather due to its protonophore activity that leads to cytoplasm acidification. We show that the known tyrosine kinase inhibitor tyrphostinA23, which is routinely used to block CME, displays similar properties, thus questioning its use as a specific inhibitor of cargo recognition by the AP-2 adaptor complex via tyrosine motif-based endocytosis signals. Furthermore, we show that cytoplasm acidification dramatically affects the dynamics and recruitment of clathrin and associated adaptors, and leads to reduction of phosphatidylinositol 4,5-biphosphate from the plasma membrane.

Plant cells maintain strict proton gradients over different membranes. Here, Dejonghe et al. show that several protonophores, including the known tyrosine kinase inhibitor TyrphostinA23, inhibit clathrin-mediated endocytosis by disturbing these gradients and causing cytoplasmic acidification.

• BRAF
• RET
• advanced thyroid cancer
• targeted therapy
• tyrosine kinase inhibitors

• Animals
• Humans
• Molecular Targeted Therapy
• Thyroid Neoplasms/drug therapy
• Thyroid Neoplasms/genetics

• EGFR
• cortical development
• neurogenesis