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

Philip East, Gavin P. Kelly, Dhruva Biswas, Michela Marani, David C. Hancock, Todd Creasy, Kris Sachsenmeier, Charles Swanton, Julian Downward () and Sophie de Carné Trécesson ()
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Philip East: The Francis Crick Institute
Gavin P. Kelly: The Francis Crick Institute
Dhruva Biswas: The Francis Crick Institute
Michela Marani: The Francis Crick Institute
David C. Hancock: The Francis Crick Institute
Todd Creasy: Oncology Research and Development, AstraZeneca
Kris Sachsenmeier: Oncology Research and Development, AstraZeneca
Charles Swanton: The Francis Crick Institute
Julian Downward: The Francis Crick Institute
Sophie de Carné Trécesson: The Francis Crick Institute

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33290-0

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