A gene expression signature associated with K-Ras addiction reveals regulators of EMT and tumor cell survival

K-Ras mutations occur frequently in epithelial cancers. Using shRNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-Ras mutations, two classes were identified—lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in “K-Ras-addicted” cancers represent candidate therapeutic targets. Expression analysis: 40 Samples representing K-Ras mutant cancer cell lines derived from various tissue types were hybridized to the Affymetrix GeneChip Human X3P Array. Copy number analysis: 10 samples representing K-Ras mutant cancer cell lines were hybridized to the Affymetrix Mapping 500K Set Arrays (250K_Nsp_SNP and 250K_Sty2_SNP). Reference data included 63 randomly chosen female samples (supplementary file Sing_etal_CopyNumber_NormalSamples.txt) from the HapMap project Affy 500K SNP data (