Our understanding of how the RAS protein family, and in particular mutant KRAS, promotes metabolic dysregulation in cancer cells has advanced substantially over the last decade. In this Review, we discuss the metabolic reprogramming mediated by oncogenic RAS in cancer and elucidate the underlying mechanisms that could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers.
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For Fig. 1 and Supplementary Tables 1–3, genome-wide cancer mutation data were compiled from databases and public resources, including AACR Genie (release 6.1-public)149, COSMIC (v90)150, cBioPortal151,152, the TCGA Research Network (https://www.cancer.gov/tcga) and NCI’s Genomic Data Commons (GDC)153, that are openly accessible to the public and are cited in the paper. The datasets derived from these resources that support the analyses and discussion presented in this article are available in the cited references. For Fig. 4a,b, previously published cancer driver mutation data were acquired from refs. 134,135 and ICGC/TCGA via controlled access through rigorous application and are available from these resources.
For Fig. 4, genes with driver mutations were applied to an in-house pathway pattern extraction pipeline (PPEP) tool described in ref. 154 and implemented in customized R scripts (https://www.r-project.org/). PPEP and corresponding databases (WPS version 2) can be downloaded from the WPS homepage. This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool155 can be made available on request from the corresponding author.
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We thank M. Yi (Frederick National Laboratory for Cancer Research, FNL) for helping search cancer databases for RAS-mutant samples and assisting with driver gene data preparation. We are grateful to D. V. Nissley (NCI RAS Initiative, FNL) for critical comments and thoughtful suggestions on the manuscript. We also thank FNL’s Scientific Publications, Graphics and Media group for their technical assistance. This work was supported by grants from NCI, HHS–National Institutes of Health, under contract number HHSN261200800001E. Research in the lab of F.M. is supported by NCI under award number R35CA197709. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.
The authors are aware of no direct conflicts with the topic of the paper; however, M.G.V.H. is a scientific advisory board member for Agios Pharmaceuticals, Aeglea Biotherapetics, iTeos Therapeutics, Faeth Therapeutics and Auron Therapeutics. F.M. is a consultant for the following companies: Amgen, Daiichi, Ideaya Biosciences, Kura Oncology, Leidos Biomedical Research, PellePharm, Pfizer, PMV Pharma and Quanta Therapeutics. F.M. is a consultant and co-founder for the following companies (with ownership interest including stock options): BridgeBio, DNAtrix, Olema Pharmaceuticals and Quartz. F.M. is the scientific director of the NCI RAS Initiative at the Frederick National Laboratory for Cancer Research/Leidos Biomedical Research. None of these affiliations represents a conflict of interest with respect to this paper.
Peer review information Nature Cancer thanks Ralph DeBerardinis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Mukhopadhyay, S., Vander Heiden, M.G. & McCormick, F. The metabolic landscape of RAS-driven cancers from biology to therapy. Nat Cancer 2, 271–283 (2021). https://doi.org/10.1038/s43018-021-00184-x
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