Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma

Understanding the details of metabolic reprogramming in hepatocellular carcinoma(HCC)is critical to improve stratification for therapy.Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts.On the basis of the identified dynamic network biomarkers,227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics:cluster 1,the pyruvate subtype,associated with upregulated pyruvate metabolism;cluster 2,the amino acid subtype,with dysregulated amino acid metabolism as the reference;cluster 3,the mixed subtype,in which lipid metabolism,amino acid metabolism,and glycan metabolism are dysregulated;and cluster 4,the glycolytic subtype,associated with the dysregulated carbohydrate metabolism.These 4 clusters showed distinct prognoses,clinical characteristics and immune cell infiltrations,which was further validated by genomic alterations,transcriptomics,metabolomics,and immune cell profiles in the other 3 independent cohorts.Besides,the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features.Importantly,cluster 2 is rich in immune cells in tumor tissues,especially programmed cell death protein 1(PD-1)-expressing cells,which may be due to the tryptophan metabolism disorders,and potentially benefiting more from PD-1 treatment.In conclusion,our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.

RAS Signaling Targeted Cancer Therapy

Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,especially the Cys12 mutation in KRAS G12C,have been identified,paving the way for irreversible inhibitor development.A series of clinical trials have proven their efficacies,and the first RAS G12C-targeting drug sotorasib(AMG-510)received approval for non-small cell lung cancer treatment in May,2021.In another approach,the development of indirect RAS inhibitors that target components of the RAS signaling pathway,including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1,MEK,AKT,and SHP2,has also made significant progress.This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs,discusses clinical challenges,and proposes beneficial strategies for RAStargeted therapy.