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Saturday, 24 October 2020 22:00–22:50: POSTER DISCUSSION SESSION: Cancer Therapeutics: Preclinical Modeling and Patient Stratification| Volume 138, SUPPLEMENT 2, S18, October 01, 2020

Stratification method based on RAS pathway oncogenic activity predicts outcome in lung adenocarcinoma

      Activating mutations in the KRAS oncogene occur in some 30% of lung adenocarcinomas, where it acts as a driver of tumour formation. However, the association between KRAS mutational status and patient outcome or response to treatment remains largely obscure in lung cancer. Other events in addition to KRAS mutation can activate RAS signalling pathways, including not only mutations in other RAS pathway genes but also alterations in gene expression that promote signalling through the RAS network. To obtain a broader measure of RAS pathway activation beyond just KRAS mutation we have used, as a surrogate for oncogenic RAS signalling, a signature of RAS-induced transcriptional activity selected to separate KRAS mutant lung cancer cell lines from RAS-pathway wild type lines. We then validated the use of this signature to measure oncogenic RAS signalling using several independent lung adenocarcinoma clinical cohorts containing both KRAS mutant and wild type tumours. More than 80% of lung adenocarcinomas showed clear transcriptional evidence of RAS pathway activation, falling into four main groupings. These are characterised by coincident mutation of STK11/LKB1 (KL), TP53 (KP), CDKN2A (KC), or no obvious co-mutation (K). 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. The highest RAS activity signature groupings showed adverse clinical outcome in both univariate and multivariate Cox proportional hazards analysis. The stratification of patients using gene expression patterns linked to oncogenic RAS signalling activity instead of genetic alterations in proto-oncogenes provides improved ability to study the functional effect of RAS on cancer progression and resistance to treatment, and could ultimately help clinical decision making.
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