RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
Date
2022-09-26ICR Author
Author
East, P
Kelly, GP
Biswas, D
Marani, M
Hancock, DC
Creasy, T
Sachsenmeier, K
Swanton, C
TRACERx consortium
Downward, J
de Carné Trécesson, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Adenocarcinoma of Lung
Genes, ras
Humans
Lung Neoplasms
Mutation
Proto-Oncogene Proteins p21(ras)
ras Proteins
Research team
Lung Cancer Group
Language
eng
Date accepted
2022-09-12
License start date
2022-09-26
Citation
Nature Communications, 2022, 13 (1), pp. 5632 -
Publisher
NATURE PORTFOLIO