The Francis Crick Institute
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RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.

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journal contribution
posted on 2022-09-30, 10:30 authored by Philip East, Gavin P Kelly, Dhruva Biswas, Michela Marani, David C Hancock, Todd Creasy, Kris Sachsenmeier, Charles Swanton, TRACERx consortium, Julian Downward, Sophie de Carné Trécesson
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.


Crick (Grant ID: 10169, Grant title: Swanton FC001169) Crick (Grant ID: 10070, Grant title: Downward FC001070) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) European Research Council (Grant ID: 834692 - RASImmune, Grant title: ERC 834692 - RASImmune) Wellcome Trust (Grant ID: 103799/A/14/Z, Grant title: WT 103799/A/14/Z) European Commission (Grant ID: 703228 - IGEMMdev, Grant title: EC 703228 - IGEMMdev)