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Journal of Medicinal Chemistry Apr 2024The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic... (Review)
Review
The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic RAS mutations disrupt this balance, favoring the active form and promoting proliferative signaling, thus rendering KRAS an appealing target for precision medicine in oncology. In 2013, Shokat and co-workers achieved a groundbreaking feat by covalently targeting a previously undiscovered allosteric pocket (switch II pocket (SWIIP)) of KRAS. This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRAS-dependent lung cancer. Recent achievements in targeting various KRAS mutants, using SWIIP as a key binding pocket, are discussed. Insights from successful KRAS targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Antineoplastic Agents; Mutation; Neoplasms; Animals; Piperazines; Pyridines; Pyrimidines
PubMed: 38621359
DOI: 10.1021/acs.jmedchem.3c02403 -
Pharmacogenomics Feb 2024
Topics: Humans; Mutation; Carcinoma, Neuroendocrine; Thyroid Neoplasms; Proto-Oncogene Proteins c-ret
PubMed: 38450459
DOI: 10.2217/pgs-2023-0234 -
JCI Insight Oct 2023Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an...
Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
Topics: Animals; Humans; Mice; Carcinoma; Colorectal Neoplasms; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Signal Transduction; Zinc Finger E-box-Binding Homeobox 1
PubMed: 37870961
DOI: 10.1172/jci.insight.164629 -
Proceedings of the National Academy of... Nov 2023The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and...
The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins were previously shown to inhibit both NF-κB and Ras activation through independent mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In this study, we have used two mouse models to establish the relevance of the κB-Ras proteins for tumorigenesis. Additionally, we have utilized a pan-cancer bioinformatics analysis to explore the role of the κB-Ras proteins in human cancers. Surprisingly, we find that the genes encoding κB-Ras 1 () and κB-Ras 2 () are rarely down-regulated in tumor samples with oncogenic Ras mutations. Reduced expression of human alone is associated with worse prognosis in at least four cancer types and linked to a network of genes implicated in tumorigenesis. Our findings provide direct evidence that loss of in human tumors that do not carry oncogenic mutations is associated with worse clinical outcomes.
Topics: Animals; Humans; Mice; Carcinogenesis; Cell Transformation, Neoplastic; Genes, ras; NF-kappa B; ras Proteins; Genes, Tumor Suppressor; Carrier Proteins
PubMed: 37931099
DOI: 10.1073/pnas.2312595120 -
Nature Reviews. Cancer Feb 2024The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF... (Review)
Review
The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.
Topics: Humans; Proto-Oncogene Proteins B-raf; Neoplastic Processes; Melanoma; Phosphorylation; Mutation; Protein Kinase Inhibitors; Cell Line, Tumor
PubMed: 38195917
DOI: 10.1038/s41568-023-00650-x -
Frontiers in Immunology 2024MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets of cancer progression. Of interest, MYC governs oncometabolism... (Review)
Review
MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets of cancer progression. Of interest, MYC governs oncometabolism through the interactions with its partners and cofactors, as well as cancer immunity via its gene targets. Recent investigations have taken interest in characterizing these interactions through multi-Omic approaches, to better understand the vastness of the MYC network. Of the several gene targets of MYC involved in either oncometabolism or oncoimmunology, few of them overlap in function. Prominent interactions have been observed with MYC and HIF-1α, in promoting glucose and glutamine metabolism and activation of antigen presentation on regulatory T cells, and its subsequent metabolic reprogramming. This review explores existing knowledge of the role of MYC in oncometabolism and oncoimmunology. It also unravels how MYC governs transcription and influences cellular metabolism to facilitate the induction of pro- or anti-tumoral immunity. Moreover, considering the significant roles MYC holds in cancer development, the present study discusses effective direct or indirect therapeutic strategies to combat MYC-driven cancer progression.
Topics: Humans; Proto-Oncogene Proteins c-myc; Neoplasms; Glycolysis
PubMed: 38390324
DOI: 10.3389/fimmu.2024.1324045 -
Methods in Molecular Biology (Clifton,... 2024RAS research has entered the world of translational and clinical science. Progress has been based on our appreciation of the role of RAS mutations in different types of...
RAS research has entered the world of translational and clinical science. Progress has been based on our appreciation of the role of RAS mutations in different types of cancer and the effects of these mutations on the biochemical, structural, and biophysical properties of the RAS proteins themselves, particularly KRAS, on which most attention has been focused. This knowledge base, while still growing, has enabled creative chemical approaches to targeting KRAS directly. Our understanding of RAS signaling pathways in normal and cancer cells plays an important role for developing RAS inhibitors but also continues to reveal new approaches to targeting RAS through disruption of signaling complexes and downstream pathways.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Mutation; Neoplasms; Signal Transduction; Antineoplastic Agents
PubMed: 38570448
DOI: 10.1007/978-1-0716-3822-4_1 -
European Journal of Medicinal Chemistry Dec 2023Kristen rat sarcoma (KRAS) is one of the most common oncogenes in human cancers. As a guanine nucleotide exchange factor, Son of Sevenless Homologue 1 (SOS1) represents... (Review)
Review
Kristen rat sarcoma (KRAS) is one of the most common oncogenes in human cancers. As a guanine nucleotide exchange factor, Son of Sevenless Homologue 1 (SOS1) represents a potential therapeutic concept for the treatment of KRAS-mutant cancers because of its activation on KRAS and downstream signaling pathways. In this review, we provide a comprehensive overview of the structure, biological function, and regulation of SOS1. We also focus on the recent advances in SOS1 inhibitors and emphasize their binding modes, structure-activity relationships and pharmacological activities. We hope that this publication can provide a comprehensive compendium on the rational design of SOS1 inhibitors.
Topics: Humans; Proto-Oncogene Proteins p21(ras); SOS1 Protein; Nuclear Family; Signal Transduction; Neoplasms
PubMed: 37778239
DOI: 10.1016/j.ejmech.2023.115828 -
Nature Communications Jan 2024Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic...
Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins p21(ras); Allelic Imbalance; Genes, ras; Cell Transformation, Neoplastic; Colorectal Neoplasms; Mutation; Tumor Microenvironment
PubMed: 38168062
DOI: 10.1038/s41467-023-44342-4 -
JAMA Otolaryngology-- Head & Neck... Sep 2023
Topics: Humans; Genomics; Proto-Oncogene Proteins c-ret; Thyroid Neoplasms; Mass Screening; Genetic Testing
PubMed: 37410478
DOI: 10.1001/jamaoto.2023.1576