PMID- 26804638 OWN - NLM STAT- MEDLINE DCOM- 20171116 LR - 20211204 IS - 1556-1380 (Electronic) IS - 1556-0864 (Linking) VI - 11 IP - 5 DP - 2016 May TI - Synergistic Activation upon MET and ALK Coamplification Sustains Targeted Therapy in Sarcomatoid Carcinoma, a Deadly Subtype of Lung Cancer. PG - 718-728 LID - S1556-0864(16)00329-4 [pii] LID - 10.1016/j.jtho.2016.01.009 [doi] AB - INTRODUCTION: Genetic alterations suitable for targeted therapy are poorly known issues in pulmonary sarcomatoid carcinoma (PSC), an uncommon and life-threatening family of non-small cell lung cancers. METHODS: Ninety-eight PSCs were assessed for MNNG HOS Transforming gene (MET) and anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by fluorescence in situ hybridization (FISH) and for relevant protein expression by immunohistochemical analysis, also taking advantage of phosphorylated (p-) antibodies. Moreover, levels of ALK and MET mRNA were also determined by real-time polymerase chain reaction and Western blot analysis for downstream activation pathways involving p-MET, p-protein kinase B, p-mitogen-activated protein kinase, p-SRC proto-oncogene tyrosine-protein kinase, and p-focal adhesion kinase (p-FAK). RESULTS: MET amplification was detected by FISH in 25 of 98 PSCs (25.6%) and ALK amplification (but not the relevant rearrangement) was found in 16 of 98 (16.3%), with all ALK-amplified tumors also showing MET amplification (p < 0.0001). Nine PSCs, however, showed MET amplification without any ALK gene alteration. ALK protein expression was always lacking, whereas MET and p-MET were confined to the relevant amplified tumors only. Increased levels of ALK and MET mRNA were detectable in tumors with no direct relationship between mRNA content, protein expression, or alterations detected by FISH. Western blot assays showed complete activation of downstream signal pathways up to p-SRC proto-oncogene tyrosine-protein kinase, and p-focal adhesion kinase recruitment in MET and ALK-coamplified tumors only, whereas isolated MET amplification, MET and ALK borderline amplification (5%-10% of tumor cells with >/=15 copies of the relevant gene), or negative tumors showing eusomy or chromosome polysomy were confined to p-mitogen-activated protein kinase, p-protein kinase B, and/or p-MET activation. Multivariate survival analysis pushed a higher percentage of MET altered cells or a higher value of MET copy gain per cell to marginally emerge for overall survival (p = 0.140) and disease-free survival (p = 0.060), respectively. CONCLUSIONS: ALK and MET seemed to act as synergistic, nonrandom coactivators of downstream signal when coamplified in a subset of patients with PSC, thus likely suggesting a combined mechanism of oncogene addiction. These alterations could be a suitable target for therapy based on specific inhibitors. CI - Copyright (c) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Pelosi, Giuseppe AU - Pelosi G AD - Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy; Department of Oncology and Hemato-Oncology, Universita degli Studi, Milan, Italy. Electronic address: giuseppe.pelosi@unimi.it. FAU - Gasparini, Patrizia AU - Gasparini P AD - Tumor Genomics Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. FAU - Conte, Davide AU - Conte D AD - Tumor Genomics Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. FAU - Fabbri, Alessandra AU - Fabbri A AD - Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. FAU - Perrone, Federica AU - Perrone F AD - Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. FAU - Tamborini, Elena AU - Tamborini E AD - Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. FAU - Pupa, Serenella M AU - Pupa SM AD - Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy. FAU - Ciravolo, Valentina AU - Ciravolo V AD - Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy. FAU - Caserini, Roberto AU - Caserini R AD - Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy. FAU - Rossi, Giulio AU - Rossi G AD - Division of Pathology, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy. FAU - Cavazza, Alberto AU - Cavazza A AD - Department of Oncology and Advanced Technology, Operative Unit of Pathologic Anatomy, Istituto Di Ricovero e Cura a Carattere Scientifico Azienda Arcispedale S. Maria Nuova, Reggio Emilia, Italy. FAU - Papotti, Mauro AU - Papotti M AD - Division of Pathology, University of Turin and Azienda Ospedaliero-Universitaria Citta della Salute e della Scienza, Torino, Italy. FAU - Nakatani, Yukio AU - Nakatani Y AD - Department of Pathology, Chiba University Graduate School of Medicine, Chiba University Hospital, Chiba, Japan. FAU - Maisonneuve, Patrick AU - Maisonneuve P AD - Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. FAU - Pastorino, Ugo AU - Pastorino U AD - Division of Thoracic Surgery, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. FAU - Sozzi, Gabriella AU - Sozzi G AD - Tumor Genomics Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy. LA - eng PT - Journal Article DEP - 20160122 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Biomarkers, Tumor) RN - 0 (MAS1 protein, human) RN - 0 (Proto-Oncogene Mas) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (MET protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Adenocarcinoma/drug therapy/genetics/metabolism/secondary MH - Adult MH - Aged MH - Aged, 80 and over MH - Anaplastic Lymphoma Kinase MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Biomarkers, Tumor MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology MH - Carcinoma, Squamous Cell/drug therapy/genetics/metabolism/secondary MH - Carcinosarcoma/*drug therapy/genetics/metabolism/secondary MH - Female MH - Follow-Up Studies MH - *Gene Amplification MH - Humans MH - Lung Neoplasms/*drug therapy/genetics/metabolism/pathology MH - Lymphatic Metastasis MH - Male MH - Middle Aged MH - Molecular Targeted Therapy MH - Mutation/genetics MH - Neoplasm Invasiveness MH - Neoplasm Recurrence, Local/drug therapy/genetics/metabolism/pathology MH - Neoplasm Staging MH - Prognosis MH - Proto-Oncogene Mas MH - Proto-Oncogene Proteins c-met/genetics/*metabolism MH - Receptor Protein-Tyrosine Kinases/*genetics OTO - NOTNLM OT - ALK OT - FISH OT - Lung OT - MET OT - Sarcomatoid carcinoma OT - Survival EDAT- 2016/01/26 06:00 MHDA- 2017/11/29 06:00 CRDT- 2016/01/26 06:00 PHST- 2015/12/12 00:00 [received] PHST- 2016/01/09 00:00 [revised] PHST- 2016/01/12 00:00 [accepted] PHST- 2016/01/26 06:00 [entrez] PHST- 2016/01/26 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] AID - S1556-0864(16)00329-4 [pii] AID - 10.1016/j.jtho.2016.01.009 [doi] PST - ppublish SO - J Thorac Oncol. 2016 May;11(5):718-728. doi: 10.1016/j.jtho.2016.01.009. Epub 2016 Jan 22.