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

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Activating KRAS mutations are found in 32% of lung adenocarcinomas (LUAD).
• KRAS mutations often lead to aggressive disease and therapy resistance, but do not reliably predict patient outcomes.
• Additional genetic events modulate RAS pathways, complicating the understanding of RAS activity in LUAD.

Purpose of the Study:

• To develop a transcriptional signature, RAS84, for a comprehensive measure of RAS pathway activation in LUAD.
• To investigate the prevalence and clinical significance of RAS pathway activation beyond KRAS mutations.
• To explore the association between RAS pathway activation and clinical outcomes, including response to chemotherapy.

Main Methods:

• Development of RAS84, a transcriptional signature to quantify RAS oncogenic activity.
• Analysis of RAS pathway activation in a broad cohort of LUAD patients, including KRAS wild-type tumors.
• Stratification of patients into groups based on RAS activity and associated genetic alterations (STK11/LKB1, TP53, CDKN2A).

Main Results:

• RAS pathway oncogenic activation was detected in 84% of LUAD cases.
• RAS activation was prevalent in KRAS wild-type tumors (65%), highlighting the need for broader activation measures.
• Four distinct patient groups were identified based on RAS activity and co-occurring genetic alterations.
• High RAS activity groups exhibited adverse clinical outcomes and diminished response to chemotherapy.

Conclusions:

• The RAS84 signature provides a more comprehensive assessment of RAS pathway activation in LUAD than KRAS mutation status alone.
• RAS pathway activation is a critical driver in a majority of LUAD, irrespective of KRAS mutation status.
• Patient stratification based on transcriptional RAS activity may improve clinical decision-making and treatment strategies for LUAD.