Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma
Introduction: EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR...
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Elsevier
2020-11-01
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| Series: | JTO Clinical and Research Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364320301077 |
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| author | Masaoki Ito, MD Jordi Codony-Servat, PhD Ana Giménez-Capitán, BSc Mireia Serra-Mitjans, MD Francisco Pérez-Ochoa, MD David Llige, BSc Imane Chaib, PhD Ramón Rami-Porta, MD Carme Obiols, MD Sergi Call, MD Manuela Iglesias, MD José Belda-Sanchis, MD Xavier Tarroch-Sarasa, MD Niki Karachaliou, MD Miguel Angel Molina-Vila, PhD Morihito Okada, MD Rafael Rosell, MD |
| author_facet | Masaoki Ito, MD Jordi Codony-Servat, PhD Ana Giménez-Capitán, BSc Mireia Serra-Mitjans, MD Francisco Pérez-Ochoa, MD David Llige, BSc Imane Chaib, PhD Ramón Rami-Porta, MD Carme Obiols, MD Sergi Call, MD Manuela Iglesias, MD José Belda-Sanchis, MD Xavier Tarroch-Sarasa, MD Niki Karachaliou, MD Miguel Angel Molina-Vila, PhD Morihito Okada, MD Rafael Rosell, MD |
| author_sort | Masaoki Ito, MD |
| collection | DOAJ |
| description | Introduction: EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD. Methods: We examined resected LUAD cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1, and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in EGFR-mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence. Results: A total of 50 of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05–3.23; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR-mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation. Conclusions: Elevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs. |
| first_indexed | 2024-12-22T16:47:17Z |
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| issn | 2666-3643 |
| language | English |
| last_indexed | 2024-12-22T16:47:17Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
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| series | JTO Clinical and Research Reports |
| spelling | doaj.art-ba1595860e4f4a8a8b44fa1c6caeb13a2022-12-21T18:19:41ZengElsevierJTO Clinical and Research Reports2666-36432020-11-0114100084Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung AdenocarcinomaMasaoki Ito, MD0Jordi Codony-Servat, PhD1Ana Giménez-Capitán, BSc2Mireia Serra-Mitjans, MD3Francisco Pérez-Ochoa, MD4David Llige, BSc5Imane Chaib, PhD6Ramón Rami-Porta, MD7Carme Obiols, MD8Sergi Call, MD9Manuela Iglesias, MD10José Belda-Sanchis, MD11Xavier Tarroch-Sarasa, MD12Niki Karachaliou, MD13Miguel Angel Molina-Vila, PhD14Morihito Okada, MD15Rafael Rosell, MD16Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, Spain; Laboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain; Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, SpainThoracic Surgery Service, University Hospital Mutua de Terrassa, Terrassa, SpainDepartment of Pathology, University Hospital Mutua de Terrassa, Terrassa, Spain; Department of Pathology, Atryshealth - Centro Medico Teknon, Barcelona, SpainLaboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, SpainLaboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, SpainThoracic Surgery Service, University Hospital Mutua de Terrassa, Terrassa, Spain; Network of Centers for Biomedical Research in Respiratory Diseases (CIBERES), Lung Cancer Group, Terrassa, SpainThoracic Surgery Service, University Hospital Mutua de Terrassa, Terrassa, SpainThoracic Surgery Service, University Hospital Mutua de Terrassa, Terrassa, Spain; Department of Morphological Sciences, School of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, SpainThoracic Surgery Service, University Hospital Mutua de Terrassa, Terrassa, SpainThoracic Surgery Service, University Hospital Mutua de Terrassa, Terrassa, SpainDepartment of Pathology, University Hospital Mutua de Terrassa, Terrassa, SpainPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, Spain; Current address: Merck Healthcare KGaA Darmstadt, Germany.Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, SpainDepartment of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanLaboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain; Institute of Oncology Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain; Corresponding author. Address for correspondence: Rafael Rosell, MD, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol Campus Can Ruti (Edifici Muntanya), Ctra. de Can Ruti, Cami de les Escoles s/n, 08916 Badalona, Barcelona, Spain.Introduction: EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD. Methods: We examined resected LUAD cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1, and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in EGFR-mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence. Results: A total of 50 of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05–3.23; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR-mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation. Conclusions: Elevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs.http://www.sciencedirect.com/science/article/pii/S2666364320301077Lung adenocarcinomaEGFRSHP2SurgeryRecurrence |
| spellingShingle | Masaoki Ito, MD Jordi Codony-Servat, PhD Ana Giménez-Capitán, BSc Mireia Serra-Mitjans, MD Francisco Pérez-Ochoa, MD David Llige, BSc Imane Chaib, PhD Ramón Rami-Porta, MD Carme Obiols, MD Sergi Call, MD Manuela Iglesias, MD José Belda-Sanchis, MD Xavier Tarroch-Sarasa, MD Niki Karachaliou, MD Miguel Angel Molina-Vila, PhD Morihito Okada, MD Rafael Rosell, MD Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma JTO Clinical and Research Reports Lung adenocarcinoma EGFR SHP2 Surgery Recurrence |
| title | Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma |
| title_full | Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma |
| title_fullStr | Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma |
| title_full_unstemmed | Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma |
| title_short | Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma |
| title_sort | src homology 2 domain containing phosphatase 2 in resected egfr mutation positive lung adenocarcinoma |
| topic | Lung adenocarcinoma EGFR SHP2 Surgery Recurrence |
| url | http://www.sciencedirect.com/science/article/pii/S2666364320301077 |
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