Effectors and potential targets selectively upregulated in human KRAS-mutant lung adenocarcinomas.
Genetic and proteomic analysis of human tumor samples can provide an important compliment to information obtained from model systems. Here we examined protein and gene expression from the Cancer Genome and Proteome Atlases (TCGA and TCPA) to characterize proteins and protein-coding genes that are selectively upregulated in KRAS-mutant lung adenocarcinomas. Phosphoprotein activation of several MAPK signaling components was considerably stronger in KRAS-mutants than any other group of tumors, even those with activating mutations in receptor tyrosine kinases (RTKs) and BRAF. Co-occurring mutations in KRAS-mutants were associated with differential activation of PDK1 and PKC-alpha. Genes showing strong activation in RNA-seq data included negative regulators of RTK/RAF/MAPK signaling along with potential oncogenic effectors including activators of Rac and Rho proteins and the receptor protein-tyrosine phosphatase genes PTPRM and PTPRE. These results corroborate RAF/MAPK signaling as an important therapeutic target in KRAS-mutant lung adenocarcinomas and pinpoint new potential targets.
Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA.
Jinyu
J
Li
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
Raffaella
R
Sordella
Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
Scott
S
Powers
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
C117307:KRAS protein, human; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D048490:raf Kinases; C490825:PTPRE protein, human; C516859:PTPRM protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D016283:Proto-Oncogene Proteins p21(ras)