title: Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors.
abstract: Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets.Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to Laser Capture Microdissection and Reverse Phase Protein Microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC).Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02).This finding was verified in an independent population by IHC (p=0.03).KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications.
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.|Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Baldelli
authors.affiliation: Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Bellezza
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinó
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Deng
authors.affiliation: Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: Vienna
authors.initials: V
authors.lastname: Ludovini
authors.affiliation: Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sidoni
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schabath
authors.affiliation: Department of Thoracic Surgery, University of Perugia, Perugia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Puma
authors.affiliation: Department of Thoracic Surgery, University of Perugia, Perugia, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Vannucci
authors.affiliation: Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Siggillino
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Liotta
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Pierobon
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005431:Florida; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D060066:Protein Interaction Maps; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D040901:Proteomics / Q000379:methods; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutation; laser capture microdissection; non-small cell lung cancers; reverse phase protein microarray; signaling networks