PUB050 Identification of Proteins Associated by Mutation Status in Non Small-Cell Lung Cancer Biopsies

Abstract

Proteins are the functional players driving both normal and disease physiology. The proteomic changes observed in lung cancer can be a consequence of mutations in cancer associated genes. Some of the most common types of mutations in lung cancer are EGFR, TP53 and KRAS mutations, known to influence treatment response. The purpose of this study was to identify proteins associated with smoking status and EGFR, TP53 and KRAS mutations in lung cancer biopsies which may serve as novel targets to overcome treatment resistance. We have performed a profiling of 300 cancer relevant proteins, of which 60 were in a phosphorylated state, using reverse phase protein arrays (RPPA). We analyzed biopsies from 80 non small-cell lung cancer biopsies and correlated the protein expression pattern with mutation status of EGFR, TP53 and KRAS, in addition to smoking status. The protein expression was correlated with mRNA expression analyzed on hybridization arrays. Ten of the samples were EGFR mutated, 9 were never-smokers, 31 TP53 mutated and 32 KRAS mutated. With a FDR < 0.001, we detected 7 proteins (ATP5A, EIF4EBP1, CCNB1, CDK1, CASP3, FN1 and CDKN2A) differentially expressed between TP53 mutated and wild type samples. Further, 4 proteins (RPS6K, CAV1, YBX1 and VIM) were higher expressed in KRAS mutated samples compared with KRAS wild type samples. For EGFR mutated samples, only the protein EGFR was upregulated. Three proteins were overexpressed in never smokers (EGFR, KRT19 and TUBA1A). A significant correlation between protein expression and mRNA expression were found for all the proteins except YBX1, ATP5A and TUBA1A (p<0.05). These results demonstrate that key driver mutations in lung cancer affect several proteins linked to the same pathway. We observed significant upregulation of the TP53 cell cycle target genes CDK1 and CCNB1 in samples with TP53 mutations. KRAS mutated samples showed an overexpression of cavolin 1 (CAV1), an important regulator of cell proliferation and metastasis, and an increased expression of the mesenchymal protein vimentin (VIM). As of today, we do not have any effective treatment targeting KRAS- and TP53- mutated cells. However, proteins associated with the mutation status may be new potential therapeutic targets to circumvent treatment resistance. In the present study, we identified both known and novel proteins associated with TP53 and KRAS mutated samples.