Oncogenic RAS activity predicts response to chemotherapy and outcome in lung adenocarcinoma

Abstract

Activating mutations in the driver oncogene KRAS occur in 32% of lung adenocarcinomas, leading to more aggressive disease and resistance to therapy in preclinical studies. However, the association between KRAS mutational status and patient outcome or response to treatment remains unclear, likely due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation beyond KRAS mutation only, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in lung adenocarcinoma. Using RAS84 to classify lung cell lines, we show that RAS transcriptional activity outperforms KRAS mutation to predict resistance to chemotherapy drugs in vitro. We report that 84% of lung adenocarcinomas show clear transcriptional evidence of RAS oncogenic activation, falling into four groups characterised by coincident mutation of STK11/LKB1, TP53 or CDKN2A. Given that 65% of these RAS pathway active tumours do not have KRAS mutations, we find that the classifications developed when considering only KRAS mutant tumours have significance in a much broader cohort of patients. Critically, patients in the highest RAS activity groups show adverse clinical outcome and reduced response to chemotherapy. The stratification of patients using gene expression patterns linked to oncogenic RAS signalling activity instead of genetic alterations in cancer genes could ultimately help clinical decision making.