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

Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response to treatment, presumably due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in LUAD. We report evidence of RAS pathway oncogenic activation in 84% of LUAD, including 65% KRAS wild-type tumours, falling into four groups characterised by coincident alteration of STK11/LKB1, TP53 or CDKN2A, suggesting that the classifications developed when considering only KRAS mutant tumours have significance in a broader cohort of patients. Critically, high RAS activity patient groups show adverse clinical outcome and reduced response to chemotherapy. Patient stratification using oncogenic RAS transcriptional activity instead of genetic alterations could ultimately assist in clinical decision-making.

Automated summary

The study found that 84% of patients with lung adenocarcinoma have oncogenic activation of the RAS signaling pathway, with a high proportion of activation even in KRAS wild-type tumors; patient groups with high RAS activity show adverse clinical outcomes and reduced response to chemotherapy. Stratifying patients based on oncogenic RAS transcriptional activity may ultimately assist in clinical decision-making.