Our understanding of how the RAS protein family, and in particular mutant KRAS promote metabolic dysregulation in cancer cells has advanced significantly over the last decade. In this Review, we discuss the metabolic reprogramming mediated by oncogenic RAS in cancer, and elucidating the underlying mechanisms could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers.
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http://dx.doi.org/10.1038/s43018-021-00184-x | DOI Listing |
Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity.
View Article and Find Full Text PDFNat Commun
January 2025
Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA.
View Article and Find Full Text PDFRAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis.
View Article and Find Full Text PDFCancers (Basel)
November 2024
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Rat Sarcoma (RAS)-driven cancers have been one of the main foci in the field of cancer science for over four decades. Despite significant improvement in understanding the biology of RAS oncogene, the method to target RAS-mutated cancers is still unclear. In recent years, the role for RAS beyond its hyperproliferation has been extensively documented.
View Article and Find Full Text PDFRAS proteins are the most frequently mutated in cancer, yet they have proved extremely difficult to target in drug discovery, largely because interfering with the interaction of RAS with its downstream effectors comes up against the challenge of protein-protein interactions (PPIs). Sequence-defined synthetic oligomers could combine the precision and customisability of synthetic molecules with the size required to address entire PPI surfaces. We have adapted the phosphoramidite chemistry of oligonucleotide synthesis to produce a library of nearly one million non-nucleosidic oligophosphoester sequences (phosphoestamers) composed of units taken from synthetic supramolecular chemistry, and used a fluorescent-activated bead sorting (FABS) process to select those that inhibit the interaction between KRAS (the most prevalent, and undrugged, RAS mutant) and RAF, a downstream effector of RAS that drives cell proliferation.
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