The Metabolic Landscape of RAS-Driven Cancers from biology to therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Mukhopadhyay S
PROVIDER: S-EPMC8045781 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing. Deficiency of mismatch repair (dMMR)/microsatellite instability (MSI) and tumor mutation burden (TMB) were also assessed. KRAS mutations were present in 48% of CRC, similarly distributed in patients younger than vs. 50 years and older. In microsatellite stable (MSS) KRAS MT tumors, composition of the TIME included higher neutrophil infiltration and lower infiltration of B cells. MSI-H/dMMR was significantly more prevalent in RAS WT (9.1%) than in KRAS MT (2.9%) CRC. In MSS CRC, TMB-high cases were significantly higher in RAS MT (3.1%) than in RAS WT (2.1%) tumors. KRAS and NRAS mutations are associated with increased neutrophil infiltration, with codon-specific differences. These results demonstrate significant differences in the TIME of RAS mutant CRC that match previous reports of immunoevasive characteristics of such tumors.
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Project description:RAS-driven cancers exhibit variable dependency on autophagy for survival; however, it is not fully understood how. In this issue of the JCI, Cheong and colleagues demonstrate that RAS-dependent elevation of casein kinase 1α (CK1α) negatively regulates autophagy at the level of autophagy gene transcription. Moreover, combined inhibition of both CK1α and autophagy reduced proliferation of RAS-driven tumors. The results of this study provide insight into the connection between mutant RAS and autophagy, and suggest targeting CK1α as a potential therapeutic strategy to modulate autophagy in RAS-driven cancers.
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Project description:HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.
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Project description:Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.
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Project description:Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.
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Project description:The rise in genomic knowledge over the past decade has revealed the molecular etiology of many diseases, and has identified intricate signaling network activity in human cancers. Genomics provides the opportunity to determine genome structure and capture the activity of thousands of molecular events concurrently, which is important for deciphering highly complex genetic diseases such as cancer. In this review, we focus on genomic efforts directed towards one of cancer's most frequently mutated networks, the RAS pathway. Genomic tools such as gene expression signatures and assessment of mutations across the RAS network enable the capture of RAS signaling complexity. Due to this high level of interaction and cross-talk within the network, efforts to target RAS signaling in the clinic have generally failed, and we currently lack the ability to directly inhibit the RAS protein with high efficacy. We propose that the use of gene expression data can identify effective treatments that broadly inhibit the RAS network as this approach measures pathway activity independent of mutation status or any single mechanism of activation. Here, we review the genomic studies that map the complexity of the RAS network in cancer, and that show how genomic measurements of RAS pathway activation can identify effective RAS inhibition strategies. We also address the challenges and future directions for treating RAS-driven tumors. In summary, genomic assessment of RAS signaling provides a level of complexity necessary to accurately map the network that matches the intricacy of RAS pathway interactions in cancer.
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Project description:Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we report that casein kinase 1? (CK1?), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy. Depletion or pharmacologic inhibition of CK1? enhanced autophagic flux in oncogenic RAS-driven human fibroblasts and multiple cancer cell lines. FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, was a critical target of CK1?, as depletion of CK1? reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1? protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1? increased phosphorylation of nuclear FOXO3A, thereby inhibiting transactivation of genes critical for RAS-induced autophagy. In both RAS-driven cancer cells and murine xenograft models, pharmacologic CK1? inactivation synergized with lysosomotropic agents to inhibit growth and promote tumor cell death. Together, our results identify a kinase feedback loop that influences RAS-dependent autophagy and suggest that targeting CK1?-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS-driven cancers.
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Project description:In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.
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Project description:The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy.
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