Effectors and potential targets selectively upregulated in human KRAS-mutant lung adenocarcinomas

Abstract

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.