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

Abstract

Activating mutations in the driver oncogene KRAS occur in 32% of lung adenocarcinomas, leading to more aggressive disease and resistance to therapy in preclinical studies. However, the association between KRAS mutational status and patient outcome or response to treatment remains unclear, likely due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation beyond KRAS mutation only, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in lung adenocarcinoma. Using RAS84 to classify lung cell lines, we show that RAS transcriptional activity outperforms KRAS mutation to predict resistance to chemotherapy drugs in vitro. We report that 84% of lung adenocarcinomas show clear transcriptional evidence of RAS oncogenic activation, falling into four groups characterised by coincident mutation of STK11/LKB1, TP53 or CDKN2A. 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. Critically, patients in the highest RAS activity groups show adverse clinical outcome and reduced response to chemotherapy. The stratification of patients using gene expression patterns linked to oncogenic RAS signalling activity instead of genetic alterations in cancer genes could ultimately help clinical decision making.

Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of primary and metastatic hepatocellular carcinoma

“…The observation that only a narrow range signalling intensity through a signal transduction pathway is compatible with tumour development raises hopes for the therapeutic efficacy of its modulation, as recently reported for stratification of HCC response to chemotherapeutic intervention based on the inactivating Rsk2 mutations that modulate the strength of the MAPK signalling (Chan et al, 2021). Similarly, only lung adenocarcinoma with a strong Ras activating signature respond to inhibitors of the MAPK Erk pathway (East et al, 2021). It remains to be seen if the Ras pathway activation signature proves to be useful for HCC stratification for defining clinically relevant treatment options.…”

“…Of note, whereas activating Ras mutations are rare in HCC (Zucman-Rossi et al, 2015), alterations in the intensity of MAPK Erk signalling participate in shaping the tumoral phenotype, as revealed by inactivating mutations of Rsk2, which is both an ERK target and a negative regulator of the pathway (Chan et al, 2021). Moreover, a recent analysis of transcriptional signatures classified HCC among tumours with significant Ras pathway activation phenotype (East et al, 2021). Because the same report highlighted the predictive value of strong versus weak Ras-driven transcriptional signature, it is relevant to model these phenotypes in HCC by controlled dosage of the Ras oncogene, as we have done in this study.…”

Mutational analysis and protein profiling predict drug sensitivity in multiple myeloma cell lines

“…With respect to RAS mutations and prediction of MEK inhibitor sensitivity, the cell line IH1 harboring a p.G12V mutation in NRAS had the highest sensitivity to trametinib, followed by the OH2 and KJON cell lines harboring NRAS p.Q61K, and KRAS p.Q61H, respectively. The presence of RAS mutations and RAS pathway activation in lung cancer was previously shown to confer the highest sensitivity to MEK inhibitors among a panel of 500 oncology drugs ( 55 ), demonstrating that RAS mutations may be indicators of sensitivity to MEK inhibitors.…”

Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma

“…Our understanding of how the availability of extracellular stimuli, or the deregulation of their sensors, translate into cellular responses is still incomplete. For example, although only 5% of the small GTPase Ras needs to be activated to give rise to full activation of Erk ( Hallberg et al, 1994 ), a clear dosage effect has been reported in pancreatic and lung tumours for activating Ras mutations ( East et al, 2021 ; Kerr et al, 2016 ; Mueller et al, 2018 ). Moreover, amplifications of the wild-type allele of Ras that give rise to an allelic imbalance and the consequent modulation of the activity of the oncogenic Ras mutants result in distinct cellular phenotypes ( Ambrogio et al, 2018 ; Bremner and Balmain, 1990 ).…”