title: Synergistic Activation upon MET and ALK Coamplification Sustains Targeted Therapy in Sarcomatoid Carcinoma, a Deadly Subtype of Lung Cancer.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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, Università degli Studi, Milan, Italy. Electronic address: giuseppe.pelosi@unimi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: Tumor Genomics Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Tumor Genomics Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Conte
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
authors.affiliation: Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciravolo
authors.affiliation: Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Caserini
authors.affiliation: Division of Pathology, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cavazza
authors.affiliation: Division of Pathology, University of Turin and Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Pathology, Chiba University Graduate School of Medicine, Chiba University Hospital, Chiba, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.affiliation: Division of Thoracic Surgery, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
authors.affiliation: Tumor Genomics Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002296:Carcinosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; FISH; Lung; MET; Sarcomatoid carcinoma; Survival