The lowest concentration at which cellular proliferation was inhibited was 6 μmol/L. Using a 30-gauge needle under direct visualization, 5 × 106 KAT-4 cells diluted in 30 μL of serum-free medium were injected subcutaneously into the cervical area. After 24 hours, gefitinib was added at various concentrations. Na+-dependent glucose cotransporter (SGLT1), reported overexpression in tumor tissues while its clinical significance was not established, and epidermal growth factor receptor (EGFR) with potential relation to SGLT1 were studied in order to investigate their clinical significance in colorectal cancer (CRC). , and the papillary cell line, NPA187, was negative for EGFR. , 12, 13, 14, 15, 16, 17) No effective treatment options currently are available to patients with ATC. Staining levels were 0, 1, and 2, respectively. EGF was not present in any of the six ATC cell lines examined, and TGF-α was present only in the DRO cell line. As a receptor tyrosine kinase, EGFR's kinase activity has been serving as the primary target for developing cancer therapeutics, namely the EGFR inhibitors including small molecules targeting its ATP binding pocket and monoclonal antibodies targeting its ligand binding domains. EGFR overexpression and cancer. NCI CPTC Antibody Characterization Program. Targeted molecular therapy offers potential treatment alternatives for patients with ATC. Expression of EGFR (ERBB, ERBB1) in cancer tissue. To initiate studies, we performed ELISA to determine the expression of growth factors TGF-α and EGF. The estimated IC50 for the apoptosis assays was 18.4 μmol/L. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. . . The mice treated with 30 and 60 mg/kg/d of gefitinib showed high levels of p-EGFR. Results of Phase I trials have indicated that this agent offers good bioavailability and tolerability (25) To develop such eligibility criteria for esophageal squ- We chose this method because the changes in absorbance as a percentage of the control and in apoptosis were linearly related to gefitinib levels in the range of the IC50. Phone: 713-745-2667; Fax: 713-794-4662; E-mail: jmyers{at}mdanderson.org. 2020 Sep;67:104925. doi: 10.1016/j.tiv.2020.104925. When treated at a concentration of 8 μmol/L (the IC50 for the MTT assays), 5.5% of the cells underwent apoptosis. Immunofluorescence microscopy was performed in a Nikon Microphot-FXA (Nikon Inc., Tokyo, Japan) equipped with an HBO 100 mercury lamp and narrow bandpass filters to individually select for green, red, and blue fluorescence (Chroma Technology Corp., Brattleboro, VT). Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. . The prognostic significance of epidermal growth factor receptor (EGFR) expression in lung cancer and, more importantly, its ability to predict response to anti-EGFR therapies, are currently subjects of active research. Bioproducts, Walkersville, MD). NIH Overexpression of EGFR is commonly found in EC and is associated with poor prognosis. The absorbance and concentration (pg/mL) were measured using a microplate reader at 450 nm. Tumor response to gefitinib was gauged using a nude mouse model of thyroid cancer. The cells were scraped and spun in a centrifuge to remove insoluble proteins. At a gefitinib concentration of 22 μmol/L, 80.7% of cells underwent apoptosis, whereas at 50 μmol/L, 94.5% of cells underwent apoptosis. This showed that gefitinib at a dosage of 150 mg/kg/d can completely block expression of p-EGFR in a nude mouse model of thyroid carcinoma. Five of the six ATC cell lines (all except DRO) stained positive for EGFR, whereas NPA187 was negative for EGFR. This suggests that inhibition of EGFR pathway maybe therapeutically beneficial to EC patients with EGFR overexpression. . Findings in human carcinoma HEp2 cells overexpressing EGFR showed nontoxic behavior in the presence of activated light (1.5 J cm−2) and in the absence of light for all BODIPYs. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Gefitinib partially blocked EGF autophosphorylation of EGFR at a concentration of 0.01 μmol/L and almost completely blocked autophosphorylation at 1 μmol/L. Our result is consistent with the former findings of high EGFR overexpression in cervical cancer [23–25]. Novel treatment strategies are needed for patients with ATC because current treatment options offer little benefit. In an in vitro study by Bergstrom et al. In preclinical studies, EGF has been shown to stimulate follicular cell proliferation and to enhance the migration and invasiveness of papillary thyroid cancer (9, 10, 11) Thyroid tumor tissue arrays representative of the entire spectrum of benign and malignant neoplasms, including ATC constructed at the head and neck tissue care facility, were used to screen for EGFR expression. . All of the blots were probed with anti–β-actin (1:1000) in 1% nonfat milk, followed by horseradish peroxidase–conjugated donkey antirabbit IgG (1:2000; Amersham) in 1% nonfat milk. Gefitinib was provided as a gift from AstraZeneca. Frozen tumors were sectioned (8 to 10 μm thick), mounted on positively charged Superfrost slides (Fisher Scientific, Houston, TX), air dried for 30 minutes, and fixed in cold acetone for 10 minutes. Although EGFR has been reported to be overexpressed in anywhere from 25% to 82% of colorectal cancers , some recent studies report protein overexpression (defined as 2+ and/or 3+ staining or in >50% of cells) in 35 to 49% of cases [7–9]. 1⇓  |  Toxicol In Vitro. MiR-887-3p Negatively Regulates STARD13 and Promotes Pancreatic Cancer Progression. Immunohistochemical results of mice subcutaneously implanted with KAT-4 ATC cell line and treated with various dosages of gefitinib. . Roengvoraphoj M, Tsongalis GJ, Dragnev KH, Rigas JR. Cancer Treat Rev. The estimated IC50 for the apoptosis assays was 18.35 μmol/L. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). The data from our tissue arrays support this finding and suggest that EGFR is highly expressed in ATC. High expression of EGFR appears to be a negative prognostic factor in multiple types of tumors, including breast cancer (19) and bladder cancer (20) ; however, few studies have examined the clinical implications of EGFR expression and location in thyroid cancer. The costs of publication of this article were defrayed in part by the payment of page charges. Some studies have demonstrated that the TGFα/EGFR autocrine loop plays an important role in polycystic kidneys and pancreatic neoplasms ( 15 , 16 ). Activation of EGFR by EGF was blocked by the addition of gefitinib. For in vitro administration, gefitinib was dissolved in dimethyl sulfoxide to a concentration of 20 mmol/L. , and show extremely aggressive behavior, leading to a high mortality rate. Patients with anaplastic thyroid cancer (ATC) face a uniformly dismal prognosis, with average 5-year survival rates of <10% and a median survival time of 3 months (3) . ISSN: 1078-0432, Sign In to Email Alerts with your Email Address. Little research has been done to examine the role of EGFR in ATC. The PCR was used to amplify exons 18, 19, and 21 from the EGFR gene using genomic DNA isolated from the following tumor-derived cell lines: papillary thyroid cancer cell line NPA187 and ATC cell lines DRO, K18, ARO, HTH-74, C643, and KAT-4. However, most studies suggest that EGFR is expressed at a higher level in thyroid cancer than in normal thyroid tissue (30 The groups treated with gefitinib at dosages of 30, 60, 90, and 150 mg/kg/d had increased tumor sizes at day 12 of 158%, 165%, 112%, and 104% of the initial tumor size, respectively. EGFR overexpression inhibited DNA damage repair, suppressed HPV-E6, restorating p53 activity and increased radiotherapy response. We assessed the potential of the EGFR inhibitor gefitinib (“Iressa,” ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis, and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel. 5)⇓ The cultures were free of Mycoplasma species. All of the other groups received gefitinib dissolved in 0.2 mL of sodium lactate solution via oral gavage. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. Tiseo M, Rossi G, Capelletti M, Sartori G, Spiritelli E, Marchioni A, Bozzetti C, De Palma G, Lagrasta C, Campanini N, Camisa R, Boni L, Franciosi V, Rindi G, Ardizzoni A. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines. The final portion of our experiments used a nude mouse model to examine the effects of various dosing schedules of gefitinib alone or in combination with paclitaxel on subcutaneously implanted KAT-4 tumors. Two methods were used to analyze the data from the study involving the model in which nude mice were injected subcutaneously. After a 3-day incubation, the number of metabolically active cells was determined by MTT assay using a 96-well microtiter plate reader (MR-5000; Dynatech Laboratories Inc., Chantilly, VA) at an absorbance of 570 nm. Furthermore, we found that the frequency of EGFR overexpression in lymph node metastases was approximately as high as in the primary lesions of cervical cancer. Thank you for sharing this Clinical Cancer Research article. The 5-year survival rate in patients with localised prostate cancer is … Cell lines are not representative for the clinical situation in this indication. Tumors were allowed to form, and after 1 month, the mice were euthanatized, and the tumors were subjected to immunohistochemical staining. Gefitinib is an EGFR tyrosine kinase inhibitor that has already been shown to have a favorable safety and tolerability profile in numerous Phase I clinical trials and therefore is a promising area of investigation in the search for effective treatments for patients with ATC. These findings suggest that the molecular blockage of EGFR activation has the potential to reduce thyroid tumor growth, making EGFR an attractive target for molecular therapy against ATC. ** Killed 6 hours after treatment. Overexpression is often a consequence of gene amplification, containing gene rearrangements Representative samples of the tissue arrays for normal thyroid tissue, papillary thyroid cancer, and ATC after staining for EGFR. Results: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. The annual prevalence of thyroid cancer in the United States was expected to be ∼22,000 people in 2003 (1) Clinical Cancer Research Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer, Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer, ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy, Cancer Therapy with a Replicating Oncolytic Adenovirus Targeting the Hypoxic Microenvironment of Tumors, 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitor, Fluvastatin, as a Novel Agent for Prophylaxis of Renal Cancer Metastasis, Experimental Therapeutics, Preclinical Pharmacology, Cancer Epidemiology, Biomarkers & Prevention, Editor's Note: Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer - August 1, 2019. Copyright © 2020 by the American Association for Cancer Research. . In the group treated with 150 mg/kg/d plus paclitaxel, tumors decreased to 98% of initial tumor size (Fig. Maximal inhibition occurred at a concentration of 14 μmol/L. Recently, several clinical therapies targeting EGFR were developed, but the eligibility criteria for these therapies is not fully established. The drug also has shown activity against a variety of human tumor cells in vitro and additive to synergistic effects when combined with radiation therapy or chemotherapy (23 Certain patient subsets are particularly responsive to EGFR TKIs. Mutations that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers, including adenocarcinoma of the lung (40% of cases), anal cancers, glioblastoma (50%) and epithelian tumors of the head and neck (80-100%). A nude mouse model of thyroid carcinoma cells injected subcutaneously was used to assess the in vivo antitumor activity of gefitinib. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. 2020 Jul 22;12:6137-6147. doi: 10.2147/CMAR.S260542. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. In summary, EGF has been shown to play a role in the pathogenesis of many types of cancer, and its receptor provides a promising target for molecular therapy. J Clin Oncol. Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC): study of a comprehensive panel of molecular markers. We do not retain these email addresses. 4)⇓ A nude mouse model was used to determine the expression of EGF, EGFR, and p-EGFR in mice implanted subcutaneously with 2.5 × 106 cells of KAT-4 ATC. Epidermal growth factor (EGF) and its receptor (EGFR) have been implicated in the pathogenesis of many different types of cancer and thus provide attractive targets for molecular therapy. Epub 2020 Jun 26. NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. eCollection 2020. The epidermal growth factor receptor (EGFR) is one of most potent oncogenes that are commonly altered in cancers. 3)⇓ However, immunohistochemical staining of sections of subcutaneously implanted KAT-4 tumors revealed that those tumors constitutively expressed EGFR and p-EGFR, as did normal murine thyroid tissue, suggesting that EGFR activation is up-regulated in vivo. The samples were diluted in sample buffer [10% SDS, 0.5 mmol/L Tris-HCl (pH 6.8), 1 mol/L dithiothreitol, 10% (v/v) glycerol, and 1% bromphenol blue] and boiled. The endpoint of interest was the percentage change from initial tumor size at day 12 of treatment. Immunohistochemical analysis was performed using rabbit anti-EGFR antibodies (Santa Cruz Biotechnology, Santa Cruz, CA). The overexpression of EGFR has been observed in both premalignant lesions and malignant tumors of the lung, and occurs in 40–80% of patients with NSCLC ( Salomon et … Finally, gefitinib alone and in combination with paclitaxel was able to reduce the growth of ATC cells in a nude mouse model of thyroid carcinoma cells injected subcutaneously. The arrays represented 14 papillary carcinomas, 6 anaplastic carcinomas, and 9 samples of nondiseased thyroid tissue. Conclusions: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Epub 2009 May 26. The epidermal growth factor receptor (EGFR) plays a pivotal role in colorectal carcinogenesis. Because patients with ATC face a dismal prognosis and have no effective treatment options, novel treatments are needed. The papillary thyroid carcinoma cell line NPA187 and the ATC cell lines KAT-4, K18, C643, HTH, ARO, and DRO were used. In papillary thyroid cancer, TGF-α and EGFR expression often are linked. After the mice were euthanatized, the tumors again were measured, and the mice were weighed. 2006 Dec 1;12(23):7117-25. doi: 10.1158/1078-0432.CCR-06-0760. Therefore in this study we aimed to evalu-ate the EGFR overexpression in TNBC in our population and its prognostic significance. At day 12, the control group of mice showed an increased tumor size of 173% of the initial tumor size. 2020 Mar 4;11:176. doi: 10.3389/fphar.2020.00176. To assess whether ATC cells produce the EGFR ligands EGF and TGF-α, ELISA was used to assess their levels in culture supernatants from six anaplastic and one papillary cancer cell lines. , Fig. Clipboard, Search History, and several other advanced features are temporarily unavailable. Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Gregorc V, Toschi L, Franklin WA, Crino L, Gazdar AF, Bunn PA Jr, Hirsch FR. Western blot analysis of KAT-4 ATC cell lines treated with various concentrations of gefitinib and subsequently exposed to EGF. . Hematoxylin and eosin staining confirmed the presence of tumors. Overexpression and/or mutations of EGFR and HER2 are well documented in a variety of solid tumors, including ovarian cancer, and have therapeutic implications (4,5). Level of staining for EGFR in normal, papillary, and anaplastic thyroid tissue from 29 human subjects. After establishing that EGFR is overexpressed in ATC and that gefitinib can suppress EGFR phosphorylation in vitro and in vivo, we then examined the effect of gefitinib on ATC cell growth and death. The most common EGFR mutations (around 90%) are either … Although the amplification and mutations of HER2 are most common in breast cancer, research over the past decade has shown that 3%–5% of CRCs harbor primary overexpression of HER2 or HER2 mutations, and the prevalence is higher in RAS and BRAF WT CRCs (reported in about 5%–14%) (according to HERACLES criteria: immunohistochemistry 3+ or 2+ in >50% cells confirmed by … Epub 2013 Jun 12. and EGFR-mediated downstream signal transduction. We showed that EGFR is increased in ATC cell lines in vitro and in vivo and in human ATCs. TGF-α was present at a level of 38.5 pg/mL per cell number in the medium from the ATC cell line DRO but was not present at an appreciable level in any of the other cell lines examined. Cells from the anaplastic cancer cell lines KAT-4, K18, C643, HTH, ARO, and DRO and from the papillary cancer cell line NPA187 were grown in serum-free medium and treated with gefitinib at concentrations ranging from 0.01 to 100 μmol/L. Triple-negative breast cancers are a poor prognostic group of breast cancers that don’t respond to conventional hormonal and her2neu targeted therapy. DRO, the only ATC cell line that did not express EGFR, also was the only tested cell line that expressed TGF-α. None of the nine normal tissue specimens stained positive for EGFR. Cells then were analyzed by flow cytometry, and the sub-G0/G1 fraction was measured using the Lysys software (Becton Dickinson, Franklin Lakes, NJ). . Grant support: The University of Texas M. D. Anderson Cancer Center Physician-Scientist Program and Multi-Disciplinary Research Program in Thyroid Cancer and by The Golfers Against Cancer. , 24) Rather, there are many different types of EGFR mutations, which vary both in the type of mutation (as described above) and in the location of the mutation in a gene. The mice treated with 150 mg/kg/QOD of gefitinib showed p-EGFR expression if euthanatized immediately before the final treatment was supposed to be given but did not express p-EGFR if euthanatized 6 hours after the final treatment, showing that a dosage of 150 mg/kg is unable to suppress EGFR phosphorylation for 48 hours. Samples again were washed three times for 5 minutes and then counterstained with 300 μg/mL Hoechst stain for 1 to 2 minutes at room temperature. USA.gov. Analysis of exons 18, 19, and 21 of EGFR showed no mutations in the six ATC cell lines tested (DRO, K18, ARO, HTH-74, C643, and KAT-4) or the papillary cell line NPA187. Cells were incubated with gefitinib for 1 hour at concentrations ranging from 0.01 to 100 μmol/L before addition of EGF (40 ng/mL) for 15 minutes. In cancer, EGFR is often amplified, overexpressed, or mutated, resulting in abnormal signaling and malignant cellular behaviors; this dysregulation has a causal role in the development and maintenance of certain human carcinomas. Di Maio M, Gridelli C, Normanno N, Perrone F, Ciardiello F. J Cell Physiol. (18) The membrane-associated NEU3 sialidase interacts with and desialylates EGFR by promoting its dimerization and downstream effectors’ activation. The groups treated with gefitinib at dosages of 30, 60, 90, and 150 mg/kg/d had increased tumor sizes at day 12 of 158%, 165%, 112%, and 104% of the initial tumor size, respectively. Adherent monolayer cultures were maintained on plastic and incubated at 37°C in 5% carbon dioxide and 95% air. Experimental Design: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. All of the cells were incubated in serum-free medium for 24 hours. All of the other mice then were placed into groups of five mice with similar average tumor volumes. The epidermal growth factor receptor (EGFR), through the MAP kinase and PI3K-Akt-mTOR axis, plays a pivotal role in colorectal cancer (CRC) pathogenesis. In the first analysis, the type I error rate was controlled at 0.017, guaranteeing that the overall type I error rate would be controlled at 0.05. Although numerous studies already have shown that gefitinib possesses clinically meaningful antitumor activity in several malignancies (28) The prognostic value of EGFR overexpression and ... Haiying Zeng1, Jieakesu Su1, Yingyong Hou1* and Lijie Tan2* Abstract Background: In view of the prominent role in cancer cell biology and alteration in substantial numbers of ESCC, defining EGFR molecular characteristics relevant to patient prognosis is of great importance. Tumor volume was calculated using the formula (A)(B2)π/6, where A was the length of the longest aspect of the tumor, and B was the length of the tumor perpendicular to A. An EGFR mutation does not refer to a single gene abnormality. Two thousand cells were grown in DMEM-10% FBS, with and without 0.01 to 100 μmol/L gefitinib, in 96-well tissue culture plates. In other words, there are many ways in which EGFR can be changed genetically. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Oral cavity squamous cell cancer line TU167 was used as a positive control, and the fibroblast line 3T3 was used as a negative control. Anaplastic thyroid carcinomas are relatively rare, constituting only 1.6% all of the thyroid cancers (2) 2013 Dec;39(8):839-50. doi: 10.1016/j.ctrv.2013.05.001. , 5) Electropherograms were analyzed for the presence of mutations. Wild-type (wt)EGFR is amplified/overexpressed in a number of tumor types, and several mutant forms of the coding gene have been found, with ΔEGFR, a deletion mutation lacking exons 2–7 of the external domain, being the most common and particularly associated with glioblastoma. The mice treated with gefitinib at a dosage of 150 mg/kg/d showed no expression of p-EGFR, whether euthanatized either immediately before or 6 hours after the final treatment (Fig. Our data show that gefitinib at a daily dosage of 150 mg/kg is able to suppress EGFR activation for 24 to 48 hours in a nude mouse model of thyroid cancer. The cultures were maintained no longer than 12 weeks after recovery from frozen stocks. High expression of EGFR appears to be a negative prognostic factor in multiple types of tumors, including breast cancer (19) Eighty-five patients of CRC who received chemotherapy in Sun Yat-sen Cancer Center … Photomontages were prepared using Adobe Photoshop software (Adobe Systems Inc., San Jose, CA). In another report, cytoplasmic immunopositivity was significantly associated with the extent of primary tumor infiltration in papillary thyroid cancer, whereas membranous staining was not. . eCollection 2020. The cells then were washed with PBS, and lysis buffer was added [1% Triton X-100, 20 mmol/L Tris (pH 8.0), 137 mmol/L sodium chloride, 10% glycerol (v/v), 2 mmol/L EDTA, 1 mmol/L phenylmethylsulfonyl fluoride, 20 μmol/L aprotinin-leupeptin-trypsin inhibitor, and 2 mmol/L sodium orthovanadate]. To assess expression of EGFR and p-EGFR in human thyroid tissue cell lines in vitro, Western blot analysis was performed on cellular lysates of the six ATC cell lines (ARO, C643, DRO, HTH, K18, and KAT-4) and the papillary cell line (NPA187). All of the cell lines injected into the mice tested free of the following pathogenic murine viruses: reovirus type 3, pneumonia virus, K virus, Theiler’s encephalitis virus, Sendai virus, minute virus, ectromelia virus, and lactate dehydrogenase virus (as assayed by M.A. In breast cancer, high levels of the EGFR [ 12 ] and c‐erbB2 [ 13 ] have been shown to correlate strongly with poor prognosis. Normal murine thyroid tissue and ATC implants expressed EGFR and p-EGFR. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC. The tumors of mice treated with 30 and 60 mg/kg QD (QD, every day) of gefitinib showed high levels of p-EGFR, whereas the tumors of mice treated with 90 mg/kg/d showed lower expression of p-EGFR. 6)⇓ The tumors of mice treated with 150 mg/kg/d of gefitinib showed no expression of p-EGFR whether the mice were euthanatized either immediately before or 6 hours after the final treatment with gefitinib. The groups then were randomized into seven treatment groups. Again were measured, and TGF-α was present only in the United States was expected to be people!, MO ) pancreatic neoplasms ( 15, 16 ) blocks activation of by! Differentially in the group treated daily with 150 mg/kg/d can completely block of. Copyright © 2020 by the addition of gefitinib caused near-total growth inhibition tolerability 25! 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