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1
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Attili I, Corvaja C, Trillo Aliaga P, Del Signore E, Spitaleri G, Passaro A, de Marinis F. Dealing with KRAS G12C inhibition in non-small cell lung cancer (NSCLC) - biology, clinical results and future directions. Cancer Treat Rev 2025; 137:102957. [PMID: 40381528 DOI: 10.1016/j.ctrv.2025.102957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 05/12/2025] [Accepted: 05/13/2025] [Indexed: 05/20/2025]
Abstract
KRAS G12C mutation occurs in ∼ 14 % of non-small cell lung cancer (NSCLC) patients and has been historically deemed undruggable, with immune-checkpoint inhibitors (ICIs) and platinum-based chemotherapy (PBC) representing the standard-of-care in the advanced setting. First-in-class, covalent KRAS G12C OFF-inhibitors sotorasib and adagrasib have revolutionized the therapeutic landscape and recently entered clinical practice. However, limited efficacy alongside toxicity profiles strengthen the need to design novel molecules and to optimize therapeutic strategies to address and overcome intrinsic and acquired resistance mechanisms. Moreover, KRAS G12C frequently co-occurs with STK11/KEAP1 mutations, that represent a negative prognostic factor, being associated with increased metastatic potential and reduced overall survival and poorer outcomes with ICIs. Furthermore, the high incidence of brain metastases is common in KRAS G12C-mutant NSCLC, and the efficacy of standard therapies and KRAS G12C inhibitors in treating or preventing central nervous system involvement is still suboptimal. In this context, novel inhibitors, such as broad-spectrum inhibitors targeting the active GTP-bound ON-state, pan-RAS ON inhibitors and allele-selective tricomplex inhibitors, have showed promising early clinical activity although their clinical utility needs to be further elucidated. In addition, targeting upstream, downstream and parallel signaling pathways through combination strategies might enhance the activity of KRAS G12C inhibitors and eventually improve clinical outcomes in this subset of NSCLC patients. Several combinations are currently under clinical investigation and promising approaches include combinations of KRAS G12C inhibitors with ICIs, SOS1, SHP2 inhibitors and PBC. Notwithstanding the potential improved efficacy of combination strategies, tolerability remains a critical challenge that must be carefully assessed and managed.
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Affiliation(s)
- Ilaria Attili
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Carla Corvaja
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Pamela Trillo Aliaga
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Ester Del Signore
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Gianluca Spitaleri
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy.
| | - Filippo de Marinis
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy
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2
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Tedeschi A, Schischlik F, Rocchetti F, Popow J, Ebner F, Gerlach D, Geyer A, Santoro V, Boghossian AS, Rees MG, Ronan MM, Roth JA, Lipp J, Samwer M, Gmachl M, Kraut N, Pearson M, Rudolph D. Pan-KRAS Inhibitors BI-2493 and BI-2865 Display Potent Antitumor Activity in Tumors with KRAS Wild-type Allele Amplification. Mol Cancer Ther 2025; 24:550-562. [PMID: 39711431 PMCID: PMC11962398 DOI: 10.1158/1535-7163.mct-24-0386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 12/24/2024]
Abstract
KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS-mutant alleles in patients with cancer. We report that KRAS wild-type (WT)-amplified tumor models are sensitive to treatment with the small-molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent antitumor activity in preclinical models of cancers driven by KRAS-mutant proteins. In this study, we used the high-throughput cellular viability Profiling Relative Inhibition Simultaneously in Mixtures assay to assess the antiproliferative activity of BI-2493 in a 900+ cancer cell line panel, expanding on our previous work. KRAS WT-amplified cancer cell lines, with a copy number >7, were identified as the most sensitive, across cell lines with any KRAS alterations, to our pan-KRAS inhibitors. Importantly, our data suggest that a KRAS "OFF" inhibitor is better suited to treat KRAS WT-amplified tumors than a KRAS "ON" inhibitor. KRAS WT amplification is common in patients with gastroesophageal cancers in which it has been shown to act as a unique cancer driver with little overlap to other actionable mutations. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent antitumor activity in vitro and in vivo in KRAS WT-amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacologic inhibition of KRAS shows antitumor activity in preclinical models of cancer with KRAS WT amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.
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Affiliation(s)
| | | | | | | | - Florian Ebner
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | | | - Antonia Geyer
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | | | | | - Matthew G. Rees
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | | | - Jesse Lipp
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | | | | | - Norbert Kraut
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Mark Pearson
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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3
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López-Merino E, Fernández-Rodrigo A, Jiang JG, Gutiérrez-Eisman S, Fernández de Sevilla D, Fernández-Medarde A, Santos E, Guerra C, Barbacid M, Esteban JA, Briz V. Different Ras isoforms regulate synaptic plasticity in opposite directions. EMBO J 2025; 44:2106-2133. [PMID: 39984756 PMCID: PMC11961722 DOI: 10.1038/s44318-025-00390-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 01/27/2025] [Accepted: 01/30/2025] [Indexed: 02/23/2025] Open
Abstract
The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function.
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Affiliation(s)
| | - Alba Fernández-Rodrigo
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain
- Inserm Université de Bordeaux, U1215 Neurocentre Magendie, Bordeaux, France
| | - Jessie G Jiang
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain
| | | | | | - Alberto Fernández-Medarde
- Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
- CIBERONC (Instituto de Salud Carlos III), Madrid, Spain
| | - Eugenio Santos
- Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
- CIBERONC (Instituto de Salud Carlos III), Madrid, Spain
| | - Carmen Guerra
- CIBERONC (Instituto de Salud Carlos III), Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
| | - Mariano Barbacid
- CIBERONC (Instituto de Salud Carlos III), Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
| | - José A Esteban
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
| | - Víctor Briz
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
- Centro Nacional de Sanidad Ambiental (Instituto de Salud Carlos III), Majadahonda, Madrid, Spain.
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4
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Foote JB, Mattox TE, Keeton AB, Chen X, Smith FT, Berry K, Holmes TW, Wang J, Huang CH, Ward A, Mitra AK, Ramirez-Alcantara V, Hardy C, Fleten KG, Flatmark K, Yoon KJ, Sarvesh S, Nagaraju GP, Bandi DSR, Maxuitenko YY, Valiyaveettil J, Carstens JL, Buchsbaum DJ, Yang J, Zhou G, Nurmemmedov E, Babic I, Gaponenko V, Abdelkarim H, Boyd MR, Gorman G, Manne U, Bae S, El-Rayes BF, Piazza GA. A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer. Cancer Res 2025; 85:956-972. [PMID: 39700396 PMCID: PMC11875992 DOI: 10.1158/0008-5472.can-24-0323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 06/04/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024]
Abstract
Activated RAS 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. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS-mutant cancer cells irrespective of the RAS mutation or isozyme. Wild-type RAS (RASWT) cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, whereas insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS-mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immunocompetent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancers. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors. Significance: ADT-007, a first-in-class pan-RAS inhibitor, has unique selectivity for cancer cells with mutant RAS or activated RAS protein and the capability to circumvent resistance to suppress tumor growth, supporting further development of ADT-007 analogs.
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Affiliation(s)
- Jeremy B. Foote
- Department of Microbiology, University of Alabama at Birmingham, Birmingham AL
| | | | - Adam B. Keeton
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
- ADT Pharmaceuticals LLC, Orange Beach, AL
| | - Xi Chen
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
- ADT Pharmaceuticals LLC, Orange Beach, AL
| | - Forrest T. Smith
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | - Kristy Berry
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | - Thomas W. Holmes
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | - Junwei Wang
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | - Chung-hui Huang
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | | | - Amit K. Mitra
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | | | - Cherlene Hardy
- Department of Microbiology, University of Alabama at Birmingham, Birmingham AL
| | - Karrianne G. Fleten
- Department of Gastroenterological Surgery, Oslo University Hospital, The Radium Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kjersti Flatmark
- Department of Gastroenterological Surgery, Oslo University Hospital, The Radium Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Karina J. Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL
| | - Sujith Sarvesh
- Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
| | - Ganji P. Nagaraju
- Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
| | | | - Yulia Y. Maxuitenko
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | - Jacob Valiyaveettil
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
| | - Julienne L. Carstens
- Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
| | - Donald J. Buchsbaum
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL
| | | | - Gang Zhou
- Georgia Cancer Center, University of Augusta, Augusta, GA
| | | | | | - Vadim Gaponenko
- Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL
| | - Hazem Abdelkarim
- Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL
| | | | - Greg Gorman
- Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University; Birmingham, AL
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Sejong Bae
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Bassel F. El-Rayes
- Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
| | - Gary A. Piazza
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL
- ADT Pharmaceuticals LLC, Orange Beach, AL
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5
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Isermann T, Sers C, Der CJ, Papke B. KRAS inhibitors: resistance drivers and combinatorial strategies. Trends Cancer 2025; 11:91-116. [PMID: 39732595 DOI: 10.1016/j.trecan.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/30/2024]
Abstract
In 1982, the RAS genes HRAS and KRAS were discovered as the first human cancer genes, with KRAS later identified as one of the most frequently mutated oncogenes. Yet, it took nearly 40 years to develop clinically effective inhibitors for RAS-mutant cancers. The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding KRASG12C inhibitors, sotorasib and adagrasib, in 2021 and 2022, respectively. However, rather than marking the end of a successful assault on the Mount Everest of cancer research, this landmark only revealed new challenges in RAS drug discovery. In this review, we highlight the progress on defining resistance mechanisms and developing combination treatment strategies to improve patient responses to KRAS therapies.
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Affiliation(s)
- Tamara Isermann
- Charité - Universitätsmedizin Berlin, Institute of Pathology, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Sers
- Charité - Universitätsmedizin Berlin, Institute of Pathology, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Channing J Der
- Charité - Universitätsmedizin Berlin, Institute of Pathology, Berlin, Germany; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bjoern Papke
- Charité - Universitätsmedizin Berlin, Institute of Pathology, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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6
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Cox AD, Der CJ. "Undruggable KRAS": druggable after all. Genes Dev 2025; 39:132-162. [PMID: 39638567 PMCID: PMC11789494 DOI: 10.1101/gad.352081.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
The three RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in cancer. KRAS is the predominant isoform mutated in cancer and is most prevalently mutated in major causes of cancer deaths including lung, colorectal, and pancreatic cancers. Despite extensive academic and industry efforts to target KRAS, it would take nearly four decades before approval of the first clinically effective KRAS inhibitors for the treatment of KRAS mutant lung cancer. We revisit past anti-KRAS strategies and painful lessons learned and then focus on the rapidly evolving landscape of direct RAS inhibitors, resistance mechanisms, and potential combination treatments.
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Affiliation(s)
- Adrienne D Cox
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Channing J Der
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
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7
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Bagheri-Yarmand R, Grubbs EG, Hofmann MC. Thyroid C-Cell Biology and Oncogenic Transformation. Recent Results Cancer Res 2025; 223:51-91. [PMID: 40102254 DOI: 10.1007/978-3-031-80396-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
The thyroid parafollicular cell, or commonly named "C-cell," functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of RB1 regulatory pathway as potential mediators of C-cell transformation. More recently, the integration of multiple biological layers of omics studies has uncovered new pathways of oncogenesis. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular targeted therapies.
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Affiliation(s)
- Rozita Bagheri-Yarmand
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth G Grubbs
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marie-Claude Hofmann
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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8
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Filis P, Salgkamis D, Matikas A, Zerdes I. Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236. Drug Discov Today 2025; 30:104250. [PMID: 39586491 DOI: 10.1016/j.drudis.2024.104250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/10/2024] [Accepted: 11/19/2024] [Indexed: 11/27/2024]
Abstract
The multi-selective tri-complex RAS(ON) inhibitors RMC-7977 and RMC-6236 signal new avenues for RAS targeting. This systematic review aims to comprehensively present the available preclinical and early clinical data on these agents. We screened Medline, Scopus, the ESMO and ASCO conference sites and ClinicalTrials.gov for related studies and found four published preclinical studies and one clinical trial. In these reports, RMC-7977 and RMC-6236 effectively drove tumor suppression, especially in non-small cell lung cancer and pancreatic ductal adenocarcinoma, and minimal effects in healthy tissue were observed. MYC amplification was reported to be a main contributor to the development of resistance. Six trials are currently ongoing, including one randomized trial, and promising results are expected from combination with other agents, such as immune-checkpoint blockers.
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Affiliation(s)
- Panagiotis Filis
- Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 451 10 Ioannina, Greece.
| | - Dimitrios Salgkamis
- Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Alexios Matikas
- Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Breast Center, Karolinska Comprehensive Cancer Center and Karolinska University Hospital, 171 76 Stockholm, Sweden
| | - Ioannis Zerdes
- Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Theme Cancer, Karolinska Comprehensive Cancer Center and Karolinska University Hospital, 171 76 Stockholm, Sweden
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9
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Yang X, Wu H. RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms. J Hematol Oncol 2024; 17:108. [PMID: 39522047 PMCID: PMC11550559 DOI: 10.1186/s13045-024-01631-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.
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Affiliation(s)
- Xiaojuan Yang
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China
| | - Hong Wu
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China.
- Liver Transplantation Center, Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China.
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10
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Foote JB, Mattox TE, Keeton AB, Chen X, Smith F, Berry KL, Holmes T, Wang J, Huang CH, Ward AB, Mitra AK, Ramirez-Alcantara V, Hardy C, Fleten KG, Flatmark K, Yoon KJ, Sarvesh S, Nagaraju GP, Bandi DSR, Maxuitenko YY, Valiyaveettil J, Carstens JL, Buchsbaum DJ, Yang J, Zhou G, Nurmemmedov E, Babic I, Gaponenko V, Abdelkarim H, Boyd MR, Gorman GS, Manne U, Bae S, El-Rayes BF, Piazza GA. A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.05.17.541233. [PMID: 38328254 PMCID: PMC10849544 DOI: 10.1101/2023.05.17.541233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS WT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RAS WT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers. SIGNIFICANCE ADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.
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11
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Ghadrdoost Nakhchi B, Kosuru R, Chrzanowska M. Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer. Int J Mol Sci 2024; 25:9853. [PMID: 39337337 PMCID: PMC11432579 DOI: 10.3390/ijms25189853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/23/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression-a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies.
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Affiliation(s)
| | - Ramoji Kosuru
- Versiti Blood Research Institute, Milwaukee, WI 53226, USA; (B.G.N.)
| | - Magdalena Chrzanowska
- Versiti Blood Research Institute, Milwaukee, WI 53226, USA; (B.G.N.)
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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12
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Péczka N, Ranđelović I, Orgován Z, Csorba N, Egyed A, Petri L, Ábrányi-Balogh P, Gadanecz M, Perczel A, Tóvári J, Schlosser G, Takács T, Mihalovits LM, Ferenczy G, Buday L, Keserű GM. Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas G12C. ACS Chem Biol 2024; 19:1743-1756. [PMID: 38991015 PMCID: PMC11334105 DOI: 10.1021/acschembio.4c00217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 06/23/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024]
Abstract
Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions. Noncovalent and covalent binding steps can be characterized by an equilibrium dissociation constant (KI) and a reaction rate constant (kinact), respectively, and they are affected by both the warhead and the scaffold of the ligand. The relative contribution of these two steps was investigated on a prototypic drug target KRASG12C, an oncogenic mutant of KRAS. We used a synthetically more accessible nonchiral core derived from ARS-1620 that was equipped with four different warheads and a previously described KRAS-specific basic side chain. Combining these structural changes, we have synthesized novel covalent KRASG12C inhibitors and tested their binding and biological effect on KRASG12C by various biophysical and biochemical assays. These data allowed us to dissect the effect of scaffold and warhead on the noncovalent and covalent binding event. Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRASG12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents.
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Affiliation(s)
- Nikolett Péczka
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
- Department
of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest 1111, Hungary
| | - Ivan Ranđelović
- Department
of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest 1122, Hungary
| | - Zoltán Orgován
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
| | - Noémi Csorba
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
- Department
of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest 1111, Hungary
| | - Attila Egyed
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
| | - László Petri
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
| | - Péter Ábrányi-Balogh
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
| | - Márton Gadanecz
- Protein
Modeling Research Group, Laboratory of Structural Chemistry and Biology, ELTE Institute of Chemistry, Budapest 1117, Hungary
- Hevesy
György PhD School of Chemistry, Eötvös
Loránd University, Pázmány Péter sétány. 1/A, Budapest 1117, Hungary
| | - András Perczel
- Protein
Modeling Research Group, Laboratory of Structural Chemistry and Biology, ELTE Institute of Chemistry, Budapest 1117, Hungary
| | - József Tóvári
- Department
of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest 1122, Hungary
| | - Gitta Schlosser
- MTA-ELTE
“Lendület”, Ion Mobility
Mass Spectrometry Research Group, Budapest 1117, Hungary
| | - Tamás Takács
- HUN-REN
Research Centre for Natural Sciences, Signal
Transduction and Functional Genomics Research Group, Budapest 1117, Hungary
- Doctoral
School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest 1117, Hungary
| | - Levente M. Mihalovits
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
| | - György
G. Ferenczy
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
| | - László Buday
- HUN-REN
Research Centre for Natural Sciences, Signal
Transduction and Functional Genomics Research Group, Budapest 1117, Hungary
| | - György M. Keserű
- Medicinal
Chemistry Research Group and National Drug Discovery and Development
Laboratory, HUN-REN Research Centre for
Natural Sciences, Budapest 1117, Hungary
- Department
of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest 1111, Hungary
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13
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Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, Olive KP. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature 2024; 629:927-936. [PMID: 38588697 PMCID: PMC11111406 DOI: 10.1038/s41586-024-07379-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 04/02/2024] [Indexed: 04/10/2024]
Abstract
Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.
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MESH Headings
- Animals
- Female
- Humans
- Mice
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Disease Models, Animal
- DNA Copy Number Variations
- Drug Resistance, Neoplasm/drug effects
- Genes, myc
- Guanosine Triphosphate/metabolism
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/genetics
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Proto-Oncogene Proteins p21(ras)/genetics
- Proto-Oncogene Proteins p21(ras)/metabolism
- Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors
- Treatment Outcome
- Xenograft Model Antitumor Assays
- Mutation
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Affiliation(s)
- Urszula N Wasko
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Tanner C Dalton
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Alvaro Curiel-Garcia
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - A Cole Edwards
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Bianca Lee
- Revolution Medicines, Redwood City, CA, USA
| | - Margo Orlen
- University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA
| | - Sha Tian
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Clint A Stalnecker
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kristina Drizyte-Miller
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Julien Dilly
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Stephen A Sastra
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Carmine F Palermo
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Marie C Hasselluhn
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Amanda R Decker-Farrell
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | | | | | - Xing Wei
- Revolution Medicines, Redwood City, CA, USA
| | - Yu C Yang
- Revolution Medicines, Redwood City, CA, USA
| | | | | | | | | | | | - Samantha B Kemp
- University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA
| | - Cynthia Clendenin
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA
| | - Rina Sor
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA
| | - William P Vostrejs
- University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA
| | - Priya S Hibshman
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Amber M Amparo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Connor Hennessey
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Matthew G Rees
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | | | | | | | - Lorenzo Tomassoni
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Basil Bakir
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Nicholas D Socci
- Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Laura E Herring
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Natalie K Barker
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Junning Wang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - James M Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - John A Chabot
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael D Kluger
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Gulam A Manji
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Kenneth Y Tsai
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Miroslav Sekulic
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Stephen M Lagana
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Andrea Califano
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- J. P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA
- Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
- Chan Zuckerberg Biohub New York, New York, NY, USA
| | | | | | | | | | | | - Scott W Lowe
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael A Badgley
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Robert H Vonderheide
- University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Ben Z Stanger
- University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA
| | - Timour Baslan
- Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Channing J Der
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Kenneth P Olive
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
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14
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Stanger BZ, Wahl GM. Cancer as a Disease of Development Gone Awry. ANNUAL REVIEW OF PATHOLOGY 2024; 19:397-421. [PMID: 37832945 PMCID: PMC11486542 DOI: 10.1146/annurev-pathmechdis-031621-025610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulates embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution.
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Affiliation(s)
- Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, Abramson Family Cancer Research Institute, and Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA;
| | - Geoffrey M Wahl
- Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA;
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15
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Danan CH, Naughton KE, Hayer KE, Vellappan S, McMillan EA, Zhou Y, Matsuda R, Nettleford SK, Katada K, Parham LR, Ma X, Chowdhury A, Wilkins BJ, Shah P, Weitzman MD, Hamilton KE. Intestinal transit-amplifying cells require METTL3 for growth factor signaling and cell survival. JCI Insight 2023; 8:e171657. [PMID: 37883185 PMCID: PMC10795831 DOI: 10.1172/jci.insight.171657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 10/25/2023] [Indexed: 10/27/2023] Open
Abstract
Intestinal epithelial transit-amplifying cells are essential stem progenitors required for intestinal homeostasis, but their rapid proliferation renders them vulnerable to DNA damage from radiation and chemotherapy. Despite these cells' critical roles in intestinal homeostasis and disease, few studies have described genes that are essential to transit-amplifying cell function. We report that RNA methyltransferase-like 3 (METTL3) is required for survival of transit-amplifying cells in the murine small intestine. Transit-amplifying cell death after METTL3 deletion was associated with crypt and villus atrophy, loss of absorptive enterocytes, and uniform wasting and death in METTL3-depleted mice. Sequencing of polysome-bound and methylated RNAs in enteroids and in vivo demonstrated decreased translation of hundreds of methylated transcripts after METTL3 deletion, particularly transcripts involved in growth factor signal transduction such as Kras. Further investigation verified a relationship between METTL3 and Kras methylation and protein levels in vivo. Our study identifies METTL3 as an essential factor supporting the homeostasis of small intestinal tissue via direct maintenance of transit-amplifying cell survival. We highlight the crucial role of RNA modifications in regulating growth factor signaling in the intestine with important implications for both homeostatic tissue renewal and epithelial regeneration.
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Affiliation(s)
- Charles H. Danan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
- Medical Scientist Training Program, Perelman School of Medicine; and
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kaitlyn E. Naughton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
| | - Katharina E. Hayer
- Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Division of Protective Immunity, Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sangeevan Vellappan
- Waksman Institute of Microbiology and
- Department of Genetics, Rutgers University, Piscataway, New Jersey, USA
- Human Genetics Institute of New Jersey, Piscataway, New Jersey, USA
| | - Emily A. McMillan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
| | - Yusen Zhou
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
- Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Rina Matsuda
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Pathobiology, School of Veterinary Medicine, and
| | - Shaneice K. Nettleford
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
| | - Kay Katada
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Louis R. Parham
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Xianghui Ma
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
| | - Afrah Chowdhury
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
| | - Benjamin J. Wilkins
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Premal Shah
- Department of Genetics, Rutgers University, Piscataway, New Jersey, USA
- Human Genetics Institute of New Jersey, Piscataway, New Jersey, USA
| | - Matthew D. Weitzman
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Protective Immunity, Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kathryn E. Hamilton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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16
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Wasko UN, Jiang J, Curiel-Garcia A, Wang Y, Lee B, Orlen M, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Dalton T, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs W, Amparo AA, Hibshman PS, Rees MG, Ronan MM, Roth JA, Bakir B, Badgley MA, Chabot JA, Kluger MD, Manji GA, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Aguirre AJ, Der CJ, Vonderheide RH, Stanger BZ, Singh M, Olive KP. Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.03.569791. [PMID: 38105998 PMCID: PMC10723304 DOI: 10.1101/2023.12.03.569791] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.
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Affiliation(s)
- Urszula N. Wasko
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | | | - Alvaro Curiel-Garcia
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | | | - Bianca Lee
- Revolution Medicines, Inc., Redwood City, CA
| | - Margo Orlen
- University of Pennsylvania Perelman School of Medicine, Department of Medicine
| | - Kristina Drizyte-Miller
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Julien Dilly
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Stephen A. Sastra
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Carmine F. Palermo
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Tanner Dalton
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Marie C. Hasselluhn
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Amanda R. Decker-Farrell
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | | | | | - Xing Wei
- Revolution Medicines, Inc., Redwood City, CA
| | - Yu C. Yang
- Revolution Medicines, Inc., Redwood City, CA
| | | | | | | | | | - Samantha B. Kemp
- University of Pennsylvania Perelman School of Medicine, Department of Medicine
| | - Cynthia Clendenin
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center
| | - Rina Sor
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center
| | - Will Vostrejs
- University of Pennsylvania Perelman School of Medicine, Department of Medicine
| | - Amber A. Amparo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Priya S. Hibshman
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | | | | | - Basil Bakir
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - Michael A. Badgley
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | - John A. Chabot
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
| | - Michael D. Kluger
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
| | - Gulam A. Manji
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
| | | | | | | | | | | | - Andrew J. Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- The Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Channing J. Der
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Robert H. Vonderheide
- University of Pennsylvania Perelman School of Medicine, Department of Medicine
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center
- Parker Institute for Cancer Immunotherapy
| | - Ben Z. Stanger
- University of Pennsylvania Perelman School of Medicine, Department of Medicine
- University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center
| | | | - Kenneth P. Olive
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
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17
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Martin-Vega A, Cobb MH. Navigating the ERK1/2 MAPK Cascade. Biomolecules 2023; 13:1555. [PMID: 37892237 PMCID: PMC10605237 DOI: 10.3390/biom13101555] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/16/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all cell types. Notably, ERK1/2 are implicated in specific processes in a context-dependent manner as in stem cells and pancreatic β-cells. Alterations in the different components of this cascade result in dysregulation of the effector kinases ERK1/2 which communicate with hundreds of substrates. Aberrant activation of the pathway contributes to a range of disorders, including cancer. This review provides an overview of the structure, activation, regulation, and mutational frequency of the different tiers of the cascade; with a particular focus on ERK1/2. We highlight the importance of scaffold proteins that contribute to kinase localization and coordinate interaction dynamics of the kinases with substrates, activators, and inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues in this field.
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Affiliation(s)
- Ana Martin-Vega
- Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390, USA;
| | - Melanie H. Cobb
- Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390, USA;
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390, USA
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18
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Shin DH, Jo JY, Choi M, Kim KH, Bae YK, Kim SS. Oncogenic KRAS mutation confers chemoresistance by upregulating SIRT1 in non-small cell lung cancer. Exp Mol Med 2023; 55:2220-2237. [PMID: 37779142 PMCID: PMC10618295 DOI: 10.1038/s12276-023-01091-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/09/2023] [Accepted: 07/04/2023] [Indexed: 10/03/2023] Open
Abstract
Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep binding pockets for specific small molecule inhibitors. Here, we demonstrated that the mRNA and protein levels of the class III histone deacetylase SIRT1 were upregulated by the KRASMut-Raf-MEK-c-Myc axis in KRASMut lung cancer cells and in lung tumors of a mouse model with spontaneous KrasG12D expression. KRASMut-induced SIRT1 bound to KRASMut and stably deacetylated KRASMut at lysine 104, which increased KRASMut activity. SIRT1 knockdown (K/D) or the SIRT1H363Y mutation increased KRASMut acetylation, which decreased KRASMut activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in KrasG12D/+;Sirt1co/co mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-KrasG12D/+;Sirt1+/+ mice and mice in each single-drug treatment group. Then, we identified p300 as a KRASMut acetyltransferase that reinforced KRASMut lysine 104 acetylation and robustly decreased KRASMut activity. KRASMut lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC‒MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRASMut activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRASMut mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRASMut lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRASMut lung cancer patients.
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Affiliation(s)
- Dong Hoon Shin
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
- Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
| | - Jeong Yeon Jo
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
- Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Minyoung Choi
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Kyung-Hee Kim
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
- Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Young-Ki Bae
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Sang Soo Kim
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
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19
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Fernandes LM, Tresemer J, Zhang J, Rios JJ, Scallan JP, Dellinger MT. Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function. Front Cell Dev Biol 2023; 11:1276333. [PMID: 37842094 PMCID: PMC10571159 DOI: 10.3389/fcell.2023.1276333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/15/2023] [Indexed: 10/17/2023] Open
Abstract
Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1 K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.
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Affiliation(s)
- Lorenzo M. Fernandes
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Jeffrey Tresemer
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Jing Zhang
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States
| | - Jonathan J. Rios
- Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX, United States
- McDermott Center for Human Growth and Development, Dallas, TX, United States
| | - Joshua P. Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Michael T. Dellinger
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United States
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
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20
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Bodhale N, Nair A, Saha B. Isoform-specific functions of Ras in T-cell development and differentiation. Eur J Immunol 2023; 53:e2350430. [PMID: 37173132 DOI: 10.1002/eji.202350430] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/02/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
Ras GTPases, well characterized for their role in oncogenesis, are the cells' molecular switches that signal to maintain immune homeostasis through cellular development, proliferation, differentiation, survival, and apoptosis. In the immune system, T cells are the central players that cause autoimmunity if dysregulated. Antigen-specific T-cell receptor (TCR) stimulation activates Ras-isoforms, which exhibit isoform-specific activator and effector requirements, functional specificities, and a selective role in T-cell development and differentiation. Recent studies show the role of Ras in T-cell-mediated autoimmune diseases; however, there is a scarcity of knowledge about the role of Ras in T-cell development and differentiation. To date, limited studies have demonstrated Ras activation in response to positive and negative selection signals and Ras isoform-specific signaling, including subcellular signaling, in immune cells. The knowledge of isoform-specific functions of Ras in T cells is essential, but still inadequate to develop the T-cell-targeted Ras isoform-specific treatment strategies for the diseases caused by altered Ras-isoform expression and activation in T cells. In this review, we discuss the role of Ras in T-cell development and differentiation, critically analyzing the isoform-specific functions.
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Affiliation(s)
| | - Arathi Nair
- National Centre for Cell Science, Pune, India
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21
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García-España A, Philips MR. Origin and Evolution of RAS Membrane Targeting. Oncogene 2023; 42:1741-1750. [PMID: 37031342 PMCID: PMC10413328 DOI: 10.1038/s41388-023-02672-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/08/2023] [Accepted: 03/15/2023] [Indexed: 04/10/2023]
Abstract
KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS proteins consist of a globular G-domain (aa1-166) and a 22-23 aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionary origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the RAS proto-oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4th exon of NRAS into the 3rd intron of KRAS. We found evolutionary conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS protein function. The persistence of four RAS isoforms through >400 million years of evolution argues strongly for differential function.
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Affiliation(s)
| | - Mark R Philips
- Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
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22
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Ren Y, Xu YP, Fan XY, Murtaza B, Wang YN, Li Z, Javed MT, Wang ZH, Li Q. Transcriptome analysis reveals key transcription factors and pathways of polian vesicle associated with cell proliferation in Vibrio splendidus-challenged Apostichopus japonicus. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2023; 46:101082. [PMID: 37146451 DOI: 10.1016/j.cbd.2023.101082] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/17/2023] [Accepted: 04/20/2023] [Indexed: 05/07/2023]
Abstract
Polian vesicle is thought to produce coelomocytes and contribute to the sea cucumber's immune system. Our previous work has indicated that polian vesicle was responsible for cell proliferation at 72 h post pathogenic challenge. However, the transcription factors related to the activation of effector factors and the molecular process behind this remained unknown. In this study, to reveal the early functions of polian vesicle in response to the microbe, a comparative transcriptome sequencing of polian vesicle in V. splendidus-challenged Apostichopus japonicus, including normal group (PV 0 h), pathogen challenging for 6 h (PV 6 h) and 12 h (PV 12 h) was performed. Compared PV 0 h to PV 6 h, PV 0 h to PV 12 h, and PV 6 h to PV 12 h, we found 69, 211, and 175 differentially expressed genes (DEGs), respectively. KEGG enrichment analysis revealed the DEGs, including several transcription factors such as fos, FOS-FOX, ATF2, egr1, KLF2, and Notch3 between PV 6 h and PV 12 h were consistently enriched in MAPK, Apelin and Notch3 signaling pathways related to cell proliferation compared with that in PV 0 h. Important DEGs involved in cell growth were chosen, and their expression patterns were almost the same as the transcriptome profile analysis by qPCR. Protein interaction network analysis indicated that two DEGs of fos and egr1 were probably significant as key candidate genes controlling cell proliferation and differentiation in polian vesicle after pathogenic infection in A. japonicus. Overall, our analysis demonstrates that polian vesicles may play an essential role in regulating proliferation via transcription factors-mediated signaling pathway in A. japonicus and provide new insights into hematopoietic modulation of polian vesicles in response to pathogen infection.
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Affiliation(s)
- Yuan Ren
- School of Bioengineering, Dalian University of Technology, Dalian 116024, China; College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng 224051, China
| | - Yong-Ping Xu
- School of Bioengineering, Dalian University of Technology, Dalian 116024, China
| | - Xu-Yuan Fan
- College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng 224051, China
| | - Bilal Murtaza
- School of Bioengineering, Dalian University of Technology, Dalian 116024, China
| | - Yi-Nan Wang
- College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng 224051, China
| | - Zhen Li
- College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng 224051, China
| | - Muhammad Tariq Javed
- Faculty of Veterinary Science, University of Agriculture, Faisalabad 38040, Pakistan
| | - Zhen-Hui Wang
- College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng 224051, China.
| | - Qiang Li
- College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng 224051, China.
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23
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Danan CH, Naughton KE, Hayer KE, Vellappan S, McMillan EA, Zhou Y, Matsuda R, Nettleford SK, Katada K, Parham LR, Ma X, Chowdhury A, Wilkins BJ, Shah P, Weitzman MD, Hamilton KE. Intestinal transit amplifying cells require METTL3 for growth factor signaling, KRAS expression, and cell survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.06.535853. [PMID: 37066277 PMCID: PMC10104132 DOI: 10.1101/2023.04.06.535853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Intestinal epithelial transit amplifying cells are essential stem progenitors required for intestinal homeostasis, but their rapid proliferation renders them vulnerable to DNA damage from radiation and chemotherapy. Despite their critical roles in intestinal homeostasis and disease, few studies have described genes that are essential to transit amplifying cell function. We report that the RNA methyltransferase, METTL3, is required for survival of transit amplifying cells in the murine small intestine. Transit amplifying cell death after METTL3 deletion was associated with crypt and villus atrophy, loss of absorptive enterocytes, and uniform wasting and death in METTL3-depleted mice. Ribosome profiling and sequencing of methylated RNAs in enteroids and in vivo demonstrated decreased translation of hundreds of unique methylated transcripts after METTL3 deletion, particularly transcripts involved in growth factor signal transduction such as Kras. Further investigation confirmed a novel relationship between METTL3 and Kras methylation and protein levels in vivo. Our study identifies METTL3 as an essential factor supporting the homeostasis of small intestinal tissue via direct maintenance of transit amplifying cell survival. We highlight the crucial role of RNA modifications in regulating growth factor signaling in the intestine, with important implications for both homeostatic tissue renewal and epithelial regeneration.
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Affiliation(s)
- Charles H. Danan
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kaitlyn E. Naughton
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Katharina E. Hayer
- Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Division of Protective Immunity, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sangeevan Vellappan
- Waksman Institute of Microbiology, Rutgers University, Piscataway, NJ, 08854, USA
- Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA
- Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
| | - Emily A. McMillan
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Yusen Zhou
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Rina Matsuda
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Shaneice K. Nettleford
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kay Katada
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Louis R. Parham
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xianghui Ma
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Afrah Chowdhury
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Benjamin J. Wilkins
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Premal Shah
- Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA
- Human Genetics Institute of New Jersey, Piscataway, NJ, 08854, USA
| | - Matthew D. Weitzman
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Protective Immunity, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine; University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kathryn E. Hamilton
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children’s Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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24
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Ras protein abundance correlates with Ras isoform mutation patterns in cancer. Oncogene 2023; 42:1224-1232. [PMID: 36864243 PMCID: PMC10079525 DOI: 10.1038/s41388-023-02638-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 03/04/2023]
Abstract
Activating mutations of Ras genes are often observed in cancer. The protein products of the three Ras genes are almost identical. However, for reasons that remain unclear, KRAS is far more frequently mutated than the other Ras isoforms in cancer and RASopathies. We have quantified HRAS, NRAS, KRAS4A and KRAS4B protein abundance across a large panel of cell lines and healthy tissues. We observe consistent patterns of KRAS > NRAS»HRAS protein expression in cells that correlate with the rank order of Ras mutation frequencies in cancer. Our data provide support for the model of a sweet-spot of Ras dosage mediating isoform-specific contributions to cancer and development. We suggest that in most cases, being the most abundant Ras isoform correlates with occupying the sweet-spot and that HRAS and NRAS expression is usually insufficient to promote oncogenesis when mutated. However, our results challenge the notion that rare codons mechanistically underpin the predominance of KRAS mutant cancers. Finally, direct measurement of mutant versus wildtype KRAS protein abundance revealed a frequent imbalance that may suggest additional non-gene duplication mechanisms for optimizing oncogenic Ras dosage.
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25
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Novel Insights into the Role of Kras in Myeloid Differentiation: Engaging with Wnt/β-Catenin Signaling. Cells 2023; 12:cells12020322. [PMID: 36672256 PMCID: PMC9857056 DOI: 10.3390/cells12020322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
Cells of the HL-60 myeloid leukemia cell line can be differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The molecular mechanisms involved in this differentiation process, however, remain unclear. This review focuses on the differentiation of HL-60 cells. Although the Ras proteins, a group of small GTP-binding proteins, are ubiquitously expressed and highly homologous, each has specific molecular functions. Kras was shown to be essential for normal mouse development, whereas Hras and Nras are not. Kras knockout mice develop profound hematopoietic defects, indicating that Kras is required for hematopoiesis in adults. The Wnt/β-catenin signaling pathway plays a crucial role in regulating the homeostasis of hematopoietic cells. The protein β-catenin is a key player in the Wnt/β-catenin signaling pathway. A great deal of evidence shows that the Wnt/β-catenin signaling pathway is deregulated in malignant tumors, including hematological malignancies. Wild-type Kras acts as a tumor suppressor during DMSO-induced differentiation of HL-60 cells. Upon DMSO treatment, Kras translocates to the plasma membrane, and its activity is enhanced. Inhibition of Kras attenuates CD11b expression. DMSO also elevates levels of GSK3β phosphorylation, resulting in the release of unphosphorylated β-catenin from the β-catenin destruction complex and its accumulation in the cytoplasm. The accumulated β-catenin subsequently translocates into the nucleus. Inhibition of Kras attenuates Lef/Tcf-sensitive transcription activity. Thus, upon treatment of HL-60 cells with DMSO, wild-type Kras reacts with the Wnt/β-catenin pathway, thereby regulating the granulocytic differentiation of HL-60 cells. Wild-type Kras and the Wnt/β-catenin signaling pathway are activated sequentially, increasing the levels of expression of C/EBPα, C/EBPε, and granulocyte colony-stimulating factor (G-CSF) receptor.
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Wang H, Liu D, Yu Y, Fang M, Gu X, Long D. Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities. Phys Chem Chem Phys 2023; 25:1045-1053. [PMID: 36537570 DOI: 10.1039/d2cp04964c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Recent advances in direct inhibition of Ras benefit from the protein's intrinsic dynamic nature that derives therapeutically vulnerable conformers bearing transiently formed cryptic pockets. Hotspot mutants of Ras are major tumor drivers and are hyperactivated in cells at variable levels, which may require allele-specific strategies for effective targeting. However, it remains unclear how the prevalent oncogenic mutations and activation states perturb the free energy landscape governing the protein dynamics and druggability. Here we characterized the nucleotide state- and allele-dependent alterations of Ras conformational dynamics using a combined NMR experimental and computational approach and constructed quantitative ensembles revealing the conservation of the cryptic SI/II-P and SII-P pockets in different states and alleles. Highly local but critical conformational reorganizations that undermine the SII-P accessibility to residue 12 have been identified as a common mechanism resulting in the low reactivities of Ras·GTP as well as Ras(G12D)·GDP with covalent SII-P inhibitors. Our results strongly support the conformational selection scenario for interactions between Ras and the previously reported binders and offer insights for the future development of state- and allele-specific, as well as pan-Ras, inhibitors.
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Affiliation(s)
- Hui Wang
- MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
| | - Dan Liu
- MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
| | - Yongkui Yu
- MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
| | - Mengqi Fang
- MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
| | - Xue Gu
- MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
| | - Dong Long
- MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. .,Department of Chemistry, University of Science and Technology of China, Hefei, China
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Scalia P, Williams SJ, Fujita-Yamaguchi Y, Giordano A. Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation. Cell Cycle 2023; 22:1-37. [PMID: 36005738 PMCID: PMC9769454 DOI: 10.1080/15384101.2022.2108117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.
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Affiliation(s)
- Pierluigi Scalia
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states,CONTACT Pierluigi Scalia ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA9102, USA
| | - Stephen J Williams
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states
| | - Yoko Fujita-Yamaguchi
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Antonio Giordano
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,School of Medical Biotechnology, University of Siena, Italy
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Abstract
The RAS family of proteins is among the most frequently mutated genes in human malignancies. In ovarian cancer (OC), the most lethal gynecological malignancy, RAS, especially KRAS mutational status at codons 12, 13, and 61, ranges from 6-65% spanning different histo-types. Normally RAS regulates several signaling pathways involved in a myriad of cellular signaling cascades mediating numerous cellular processes like cell proliferation, differentiation, invasion, and death. Aberrant activation of RAS leads to uncontrolled induction of several downstream signaling pathways such as RAF-1/MAPK (mitogen-activated protein kinase), PI3K phosphoinositide-3 kinase (PI3K)/AKT, RalGEFs, Rac/Rho, BRAF (v-Raf murine sarcoma viral oncogene homolog B), MEK1 (mitogen-activated protein kinase kinase 1), ERK (extracellular signal-regulated kinase), PKB (protein kinase B) and PKC (protein kinase C) involved in cell proliferation as well as maintenance pathways thereby driving tumorigenesis and cancer cell propagation. KRAS mutation is also known to be a biomarker for poor outcome and chemoresistance in OC. As a malignancy with several histotypes showing varying histopathological characteristics, we focus on reviewing recent literature showcasing the involvement of oncogenic RAS in mediating carcinogenesis and chemoresistance in OC and its subtypes.
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Affiliation(s)
- Lubna Therachiyil
- Hamad Medical Corporation, Doha, Qatar, 3050, Qatar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, 2713, Qatar
| | - Anjana Anand
- Hamad Medical Corporation, Doha, Qatar, 3050, Qatar
| | | | | | - Hesham M. Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, 2713, Qatar
| | - Shahab Uddin
- Hamad Medical Corporation, Doha, Qatar, 3050, Qatar
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Nuevo-Tapioles C, Philips MR. The role of KRAS splice variants in cancer biology. Front Cell Dev Biol 2022; 10:1033348. [PMID: 36393833 PMCID: PMC9663995 DOI: 10.3389/fcell.2022.1033348] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022] Open
Abstract
The three mammalian RAS genes (HRAS, NRAS and KRAS) encode four proteins that play central roles in cancer biology. Among them, KRAS is mutated more frequently in human cancer than any other oncogene. The pre-mRNA of KRAS is alternatively spliced to give rise to two products, KRAS4A and KRAS4B, which differ in the membrane targeting sequences at their respective C-termini. Notably, both KRAS4A and KRAS4B are oncogenic when KRAS is constitutively activated by mutation in exon 2 or 3. Whereas KRAS4B is the most studied oncoprotein, KRAS4A is understudied and until recently considered relatively unimportant. Emerging work has confirmed expression of KRAS4A in cancer and found non-overlapping functions of the splice variants. The most clearly demonstrated of these is direct regulation of hexokinase 1 by KRAS4A, suggesting that the metabolic vulnerabilities of KRAS-mutant tumors may be determined in part by the relative expression of the splice variants. The aim of this review is to address the most relevant characteristics and differential functions of the KRAS splice variants as they relate to cancer onset and progression.
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Laskovs M, Partridge L, Slack C. Molecular inhibition of RAS signalling to target ageing and age-related health. Dis Model Mech 2022; 15:276620. [PMID: 36111627 PMCID: PMC9510030 DOI: 10.1242/dmm.049627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The RAS/MAPK pathway is a highly conserved signalling pathway with a well-established role in cancer. Mutations that hyperactivate this pathway are associated with unregulated cell proliferation. Evidence from a range of model organisms also links RAS/MAPK signalling to ageing. Genetic approaches that reduce RAS/MAPK signalling activity extend lifespan and also improve healthspan, delaying the onset and/or progression of age-related functional decline. Given its role in cancer, therapeutic interventions that target and inhibit this pathway's key components are under intense investigation. The consequent availability of small molecule inhibitors raises the possibility of repurposing these compounds to ameliorate the deleterious effects of ageing. Here, we review evidence that RAS/MAPK signalling inhibitors already in clinical use, such as trametinib, acarbose, statins, metformin and dihydromyricetin, lead to lifespan extension and to improved healthspan in a range of model systems. These findings suggest that the repurposing of small molecule inhibitors of RAS/MAPK signalling might offer opportunities to improve health during ageing, and to delay or prevent the development of age-related disease. However, challenges to this approach, including poor tolerance to treatment in older adults or development of drug resistance, first need to be resolved before successful clinical implementation. Summary: This Review critically discusses the links between RAS signalling and ageing, and how RAS inhibitors could extend lifespan and enhance healthspan.
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Affiliation(s)
- Mihails Laskovs
- School of Biosciences, College of Health and Life Sciences, Aston University 1 , Birmingham B4 7ET , UK
| | - Linda Partridge
- Institute of Healthy Ageing 2 , Department of Genetics, Evolution and Environment , , Darwin Building, Gower Street, London WC1E 6BT , UK
- University College London 2 , Department of Genetics, Evolution and Environment , , Darwin Building, Gower Street, London WC1E 6BT , UK
- Max Planck Institute for Biology of Ageing 3 , Joseph-Stelzmann-Strasse 9b, 50931 Cologne , Germany
| | - Cathy Slack
- School of Biosciences, College of Health and Life Sciences, Aston University 1 , Birmingham B4 7ET , UK
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Sun P, Wang H, Liu L, Guo K, Li X, Cao Y, Ko C, Lan ZJ, Lei Z. Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility. Front Physiol 2022; 13:991719. [PMID: 36060690 PMCID: PMC9437434 DOI: 10.3389/fphys.2022.991719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and its downstream targets in gonadal steroidogenic cells for the development and homeostasis of reproductive functions remain to be determined. To understand the functions of KRAS signaling in gonadal theca and interstitial cells, we generated a Kras mutant (tKrasMT) mouse line that selectively expressed a constitutively active KrasG12D in these cells. KrasG12D expression in ovarian theca cells did not block follicle development to the preovulatory stage. However, tKrasMT females failed to ovulate and thus were infertile. The phosphorylated ERK1/2 and forkhead box O1 (FOXO1) and total FOXO1 protein levels were markedly reduced in tKrasMT theca cells. KrasG12D expression in theca cells also curtailed the phosphorylation of ERK1/2 and altered the expression of several ovulation-related genes in gonadotropin-primed granulosa cells. To uncover downstream targets of KRAS/FOXO1 signaling in theca cells, we found that the expression of bone morphogenic protein 7 (Bmp7), a theca-specific factor involved in ovulation, was significantly elevated in tKrasMT theca cells. Chromosome immunoprecipitation assays demonstrated that FOXO1 interacted with the Bmp7 promoter containing forkhead response elements and that the binding activity was attenuated in tKrasMT theca cells. Moreover, Foxo1 knockdown caused an elevation, whereas Foxo1 overexpression resulted in an inhibition of Bmp7 expression, suggesting that KRAS signaling regulates FOXO1 protein levels to control Bmp7 expression in theca cells. Thus, the anovulation phenotype observed in tKrasMT mice may be attributed to aberrant KRAS/FOXO1/BMP7 signaling in theca cells. Our work provides the first in vivo evidence that maintaining normal KRAS activity in ovarian theca cells is crucial for ovulation and female fertility.
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Affiliation(s)
- Penghao Sun
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
| | - Hongliang Wang
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Zhenmin Lei, ; Hongliang Wang,
| | - Lingyun Liu
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
| | - Kaimin Guo
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
| | - Xian Li
- Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY, United States
| | - Yin Cao
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
| | - Chemyong Ko
- Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Zi-Jian Lan
- Birth Defects Center, University of Louisville School of Dentistry, Louisville, KY, United States
| | - Zhenmin Lei
- Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY, United States
- *Correspondence: Zhenmin Lei, ; Hongliang Wang,
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Abstract
In this review, I provide a brief history of the discovery of RAS and the GAPs and GEFs that regulate its activity from a personal perspective. Much of this history has been driven by technological breakthroughs that occurred concurrently, such as molecular cloning, cDNA expression to analyze RAS proteins and their structures, and application of PCR to detect mutations. I discuss the RAS superfamily and RAS proteins as therapeutic targets, including recent advances in developing RAS inhibitors. I also describe the role of the RAS Initiative at Frederick National Laboratory for Cancer Research in advancing development of RAS inhibitors and providing new insights into signaling complexes and interaction of RAS proteins with the plasma membrane.
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Affiliation(s)
- Frank McCormick
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States; Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
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33
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Abstract
The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.
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Affiliation(s)
- Katie E Hebron
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Edjay Ralph Hernandez
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Marielle E Yohe
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1. Oncogene 2022; 41:280-292. [PMID: 34743207 DOI: 10.1038/s41388-021-02097-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/27/2021] [Accepted: 10/25/2021] [Indexed: 12/27/2022]
Abstract
We previously found the SLC3A2-NRG1 (S-N) fusion gene in a lung adenocarcinoma specimen without known driver mutations and validated this in 59 invasive mucinous adenocarcinoma (IMA) samples. Interestingly, KRAS mutation coexisted (62.5%) in 10 out of 16 NRG1 fusions. In this study, we examined the role of mutant KRAS in regulating the S-N fusion protein in KRAS mutant (H358) and wild-type (Calu-3) cells. KRAS mutation-mediated increase in MEK1/2 and ERK1/2 activity enhanced disintegrin and metalloproteinase (ADAM)17 activity, which increased the shedding of NRG1 from the S-N fusion protein. The cleavage of NRG1 also increased the phosphorylation of ERBB2-ERBB3 heterocomplex receptors and their downstream signalling pathways, including PI3K/Akt/mTOR, even under activated KRAS mutation signalling. The concurrence of S-N fusion and KRAS mutation synergistically increased cell proliferation, colony formation, tumour growth, and the cells' resistance to EGFR kinase inhibitors more than KRAS mutation alone. Targeted inhibition of MEK1/2, and ADAM17 significantly induced apoptosis singly and when combined with each mutation singly or with chemotherapy in both the concurrent KRAS mutant and S-N fusion xenograft and lung orthotopic models. Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion.
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35
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Motta R, Cabezas-Camarero S, Torres-Mattos C, Riquelme A, Calle A, Montenegro P, Sotelo MJ. Personalizing first-line treatment in advanced colorectal cancer: Present status and future perspectives. J Clin Transl Res 2021; 7:771-785. [PMID: 34988329 PMCID: PMC8710355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/12/2021] [Accepted: 11/12/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Colorectal cancer is one of the most frequent neoplasms worldwide, and the majority of patients are diagnosed in advanced stages. Metastatic colorectal cancer (mCRC) harbors several mutations with different prognostic and predictive values; KRAS, NRAS, and BRAF mutations are the best known. Indeed, RAS and BRAF molecular status are associated with a different response to monoclonal antibodies (Anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor agents), which are usually added to chemotherapy in first-line, and thus allow to select the optimal therapy for patients with mCRC. Furthermore, sidedness is an important predictive and prognostic factor in mCRC, which is explained by the different molecular profile of left and right-sided tumors. Recently, microsatellite instability-high has emerged as a predictive factor of response and survival from immune checkpoint inhibitors in mCRC. Finally, several other alterations have been described in lower frequencies, such as human epidermal growth factor receptor-2 overexpression/amplification, PIK3CA pathway alterations, phosphatase and tension homolog loss, and hepatocyte growth factor/mesenchymal-epithelial transition factor pathway dysregulation, with several targeted therapies already demonstrating activity or being tested in currently ongoing clinical trials. AIM To review the importance of studying the predictive and prognostic roles of the molecular profile of mCRC, the changes occurred in recent years and how they would potentially change in the near future, to guide physicians in treatment decisions. RELEVANCE FOR PATIENTS Today, several different therapeutic options can be offered to patients in the first-line setting of mCRC. Therapies at present approved or under investigation in clinical trials will be thoroughly reviewed, with special emphasis on the molecular rationale behind them. Understanding the molecular status, resistance mechanisms and potential new druggable targets may allow physicians to choose the best therapeutic option in the first-line mCRC.
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Affiliation(s)
- Rodrigo Motta
- Department of Medical Oncology, Aliada Cancer Center, Lima, Peru
- Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
| | - Santiago Cabezas-Camarero
- Department of Medical Oncology, Hospital Universitario Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain
| | - Cesar Torres-Mattos
- Department of Medical Oncology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru
- Oncological Research Unit, Clínica San Gabriel, Lima, Peru
| | - Alejandro Riquelme
- Department of Medical Oncology, Hospital Universitario Infanta Cristina, Madrid, Spain
| | - Ana Calle
- Department of Medical Oncology, Aliada Cancer Center, Lima, Peru
- Department of Medical Oncology, Hospital María Auxiliadora, Lima, Peru
| | - Paola Montenegro
- Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
- Auna-OncoSalud Network, Lima, Peru
| | - Miguel J. Sotelo
- Department of Medical Oncology, Aliada Cancer Center, Lima, Peru
- Oncological Research Unit, Clínica San Gabriel, Lima, Peru
- Department of Medical Oncology, Hospital María Auxiliadora, Lima, Peru
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Drosten M, Barbacid M. Targeting KRAS mutant lung cancer: light at the end of the tunnel. Mol Oncol 2021; 16:1057-1071. [PMID: 34951114 PMCID: PMC8895444 DOI: 10.1002/1878-0261.13168] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/02/2021] [Accepted: 12/21/2021] [Indexed: 11/26/2022] Open
Abstract
For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen‐activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK‐independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.
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Affiliation(s)
- Matthias Drosten
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Mariano Barbacid
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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Mouse Models of Frequently Mutated Genes in Acute Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13246192. [PMID: 34944812 PMCID: PMC8699817 DOI: 10.3390/cancers13246192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/24/2021] [Accepted: 11/30/2021] [Indexed: 01/19/2023] Open
Abstract
Acute myeloid leukemia is a clinically and biologically heterogeneous blood cancer with variable prognosis and response to conventional therapies. Comprehensive sequencing enabled the discovery of recurrent mutations and chromosomal aberrations in AML. Mouse models are essential to study the biological function of these genes and to identify relevant drug targets. This comprehensive review describes the evidence currently available from mouse models for the leukemogenic function of mutations in seven functional gene groups: cell signaling genes, epigenetic modifier genes, nucleophosmin 1 (NPM1), transcription factors, tumor suppressors, spliceosome genes, and cohesin complex genes. Additionally, we provide a synergy map of frequently cooperating mutations in AML development and correlate prognosis of these mutations with leukemogenicity in mouse models to better understand the co-dependence of mutations in AML.
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38
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Haidar M, Jacquemin P. Past and Future Strategies to Inhibit Membrane Localization of the KRAS Oncogene. Int J Mol Sci 2021; 22:13193. [PMID: 34947990 PMCID: PMC8707736 DOI: 10.3390/ijms222413193] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/02/2021] [Accepted: 12/04/2021] [Indexed: 12/13/2022] Open
Abstract
KRAS is one of the most studied oncogenes. It is well known that KRAS undergoes post-translational modifications at its C-terminal end. These modifications are essential for its membrane location and activity. Despite significant efforts made in the past three decades to target the mechanisms involved in its membrane localization, no therapies have been approved and taken into the clinic. However, many studies have recently reintroduced interest in the development of KRAS inhibitors, either by directly targeting KRAS or indirectly through the inhibition of critical steps involved in post-translational KRAS modifications. In this review, we summarize the approaches that have been applied over the years to inhibit the membrane localization of KRAS in cancer and propose a new anti-KRAS strategy that could be used in clinic.
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Affiliation(s)
| | - Patrick Jacquemin
- De Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium;
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39
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Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer. Int J Mol Sci 2021; 22:ijms222212402. [PMID: 34830283 PMCID: PMC8623813 DOI: 10.3390/ijms222212402] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 01/23/2023] Open
Abstract
RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.
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Motta M, Fasano G, Gredy S, Brinkmann J, Bonnard AA, Simsek-Kiper PO, Gulec EY, Essaddam L, Utine GE, Guarnetti Prandi I, Venditti M, Pantaleoni F, Radio FC, Ciolfi A, Petrini S, Consoli F, Vignal C, Hepbasli D, Ullrich M, de Boer E, Vissers LELM, Gritli S, Rossi C, De Luca A, Ben Becher S, Gelb BD, Dallapiccola B, Lauri A, Chillemi G, Schuh K, Cavé H, Zenker M, Tartaglia M. SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. Am J Hum Genet 2021; 108:2112-2129. [PMID: 34626534 DOI: 10.1016/j.ajhg.2021.09.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/14/2021] [Indexed: 12/16/2022] Open
Abstract
Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.
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Affiliation(s)
- Marialetizia Motta
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Giulia Fasano
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Sina Gredy
- Institute of Physiology, University of Wuerzburg, 97070 Wuerzburg, Germany
| | - Julia Brinkmann
- Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany
| | - Adeline Alice Bonnard
- Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, 75019 Paris, France; INSERM UMR 1131, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
| | - Pelin Ozlem Simsek-Kiper
- Department of Pediatric Genetics, Hacettepe University Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey
| | - Elif Yilmaz Gulec
- Department of Medical Genetics, Health Sciences University, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, 34303 Istanbul, Turkey
| | - Leila Essaddam
- Department of Pediatrics-PUC, Béchir Hamza Children's Hospital, Faculty of Medicine, University of Tunis El Manar, Jebbari 1007, Tunis, Tunisia
| | - Gulen Eda Utine
- Department of Pediatric Genetics, Hacettepe University Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey
| | - Ingrid Guarnetti Prandi
- Dipartimento per la Innovazione nei Sistemi Biologici, Agroalimentari e Forestali, Università Della Tuscia, 01100 Viterbo, Italy
| | - Martina Venditti
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Francesca Pantaleoni
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Francesca Clementina Radio
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Andrea Ciolfi
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Stefania Petrini
- Confocal Microscopy Core Facility, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy
| | - Federica Consoli
- Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Cédric Vignal
- Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, 75019 Paris, France
| | - Denis Hepbasli
- Institute of Physiology, University of Wuerzburg, 97070 Wuerzburg, Germany
| | - Melanie Ullrich
- Institute of Physiology, University of Wuerzburg, 97070 Wuerzburg, Germany
| | - Elke de Boer
- Department of Human Genetics, Radboudumc, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 GA Nijmegen, the Netherlands
| | - Lisenka E L M Vissers
- Department of Human Genetics, Radboudumc, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 GA Nijmegen, the Netherlands
| | - Sami Gritli
- Department of Immunology, Pasteur Institute of Tunis, 1002 Tunis-Belvédère, Tunisia
| | - Cesare Rossi
- Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Alessandro De Luca
- Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Saayda Ben Becher
- Department of Pediatrics-PUC, Béchir Hamza Children's Hospital, Faculty of Medicine, University of Tunis El Manar, Jebbari 1007, Tunis, Tunisia
| | - Bruce D Gelb
- Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bruno Dallapiccola
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Antonella Lauri
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
| | - Giovanni Chillemi
- Dipartimento per la Innovazione nei Sistemi Biologici, Agroalimentari e Forestali, Università Della Tuscia, 01100 Viterbo, Italy; Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari, Centro Nazionale Delle Ricerche, 70126 Bari, Italy
| | - Kai Schuh
- Institute of Physiology, University of Wuerzburg, 97070 Wuerzburg, Germany
| | - Hélène Cavé
- Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, 75019 Paris, France; INSERM UMR 1131, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
| | - Martin Zenker
- Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
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Surve S, Watkins SC, Sorkin A. EGFR-RAS-MAPK signaling is confined to the plasma membrane and associated endorecycling protrusions. J Cell Biol 2021; 220:212639. [PMID: 34515735 PMCID: PMC8563293 DOI: 10.1083/jcb.202107103] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
The subcellular localization of RAS GTPases defines the operational compartment of the EGFR-ERK1/2 signaling pathway within cells. Hence, we used live-cell imaging to demonstrate that endogenous KRAS and NRAS tagged with mNeonGreen are predominantly localized to the plasma membrane. NRAS was also present in the Golgi apparatus and a tubular, plasma-membrane derived endorecycling compartment, enriched in recycling endosome markers (TERC). In EGF-stimulated cells, there was essentially no colocalization of either mNeonGreen-KRAS or mNeonGreen-NRAS with endosomal EGFR, which, by contrast, remained associated with endogenous Grb2-mNeonGreen, a receptor adaptor upstream of RAS. ERK1/2 activity was diminished by blocking cell surface EGFR with cetuximab, even after most ligand-bound, Grb2-associated EGFRs were internalized. Endogenous mCherry-tagged RAF1, an effector of RAS, was recruited to the plasma membrane, with subsequent accumulation in mNG-NRAS–containing TERCs. We propose that a small pool of surface EGFRs sustain signaling within the RAS-ERK1/2 pathway and that RAS activation persists in TERCs, whereas endosomal EGFR does not significantly contribute to ERK1/2 activity.
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Affiliation(s)
- Sachin Surve
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Simon C Watkins
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Alexander Sorkin
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer 2021; 20:128. [PMID: 34607583 PMCID: PMC8489073 DOI: 10.1186/s12943-021-01422-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023] Open
Abstract
Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
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Affiliation(s)
- Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform. Proc Natl Acad Sci U S A 2021; 118:2023112118. [PMID: 34301865 DOI: 10.1073/pnas.2023112118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.
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Abstract
KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. In this review, we summarize the current data about the importance of membrane-anchorage of K-Ras and provide a critical evaluation of this targeting paradigm focusing mainly on prenylation inhibition. Additionally, we performed a RAS mutation-specific analysis of prenylation-related drug sensitivity data from a publicly available database (https://depmap.org/repurposing/) of three classes of prenylation inhibitors: statins, N-bisphosphonates, and farnesyl-transferase inhibitors. We observed significant differences in sensitivity to N-bisphosphonates and farnesyl-transferase inhibitors depending on KRAS mutational status and tissue of origin. These observations emphasize the importance of factors affecting efficacy of prenylation inhibition, like distinct features of different KRAS mutations, tissue-specific mutational patterns, K-Ras turnover, and changes in regulation of prenylation process. Finally, we enlist the factors that might be responsible for the large discrepancy between the outcomes in preclinical and clinical studies including methodological pitfalls, the incomplete understanding of K-Ras protein turnover, and the variation of KRAS dependency in KRAS mutant tumors.
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45
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Chen WC, To MD, Westcott PMK, Delrosario R, Kim IJ, Philips M, Tran Q, Bollam SR, Goodarzi H, Bayani N, Mirzoeva O, Balmain A. Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells. Nat Commun 2021; 12:4288. [PMID: 34257283 PMCID: PMC8277813 DOI: 10.1038/s41467-021-24498-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 06/14/2021] [Indexed: 12/30/2022] Open
Abstract
The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics.
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Affiliation(s)
- Wei-Ching Chen
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Minh D To
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Peter M K Westcott
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
- MIT Koch Institute for Integrative Cancer Research, Cambridge, MA, USA
| | - Reyno Delrosario
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Il-Jin Kim
- Guardant Health, Redwood City, California, USA
| | - Mark Philips
- NYU Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Quan Tran
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Saumya R Bollam
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Hani Goodarzi
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - Nora Bayani
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Olga Mirzoeva
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Allan Balmain
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
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RASless MEFs as a Tool to Study RAS-Dependent and RAS-Independent Functions. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2021; 2262:335-346. [PMID: 33977488 DOI: 10.1007/978-1-0716-1190-6_21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
RAS proteins are key players in multiple cellular processes. To study the role of RAS proteins individually or in combination, we have developed MEFs that can be rendered RASless, i.e., devoid of all endogenous RAS isoforms. These cells have significantly contributed to our understanding of the requirements for RAS functions in cell proliferation as well as their implications in diverse cellular processes. Here, we describe methods using RASless MEFs to study RAS-dependent cellular activities with special emphasis on proliferation. We provide the details to identify inducers of RAS-independent proliferation in colony assays. We recommend following these stringent guidelines to avoid false-positive results. Moreover, this protocol can be adapted to generate RASless MEFs ectopically expressing RAS variants to interrogate their function in the absence of endogenous RAS isoforms or to perform experiments in the absence of RAS. Finally, we also describe protocols to generate and use RASless MEFs for cell cycle analyses using the FUCCI cell cycle indicator.
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Henkels KM, Rehl KM, Cho KJ. Blocking K-Ras Interaction With the Plasma Membrane Is a Tractable Therapeutic Approach to Inhibit Oncogenic K-Ras Activity. Front Mol Biosci 2021; 8:673096. [PMID: 34222333 PMCID: PMC8244928 DOI: 10.3389/fmolb.2021.673096] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
Ras proteins are membrane-bound small GTPases that promote cell proliferation, differentiation, and apoptosis. Consistent with this key regulatory role, activating mutations of Ras are present in ∼19% of new cancer cases in the United States per year. K-Ras is one of the three ubiquitously expressed isoforms in mammalian cells, and oncogenic mutations in this isoform account for ∼75% of Ras-driven cancers. Therefore, pharmacological agents that block oncogenic K-Ras activity would have great clinical utility. Most efforts to block oncogenic Ras activity have focused on Ras downstream effectors, but these inhibitors only show limited clinical benefits in Ras-driven cancers due to the highly divergent signals arising from Ras activation. Currently, four major approaches are being extensively studied to target K-Ras–driven cancers. One strategy is to block K-Ras binding to the plasma membrane (PM) since K-Ras requires the PM binding for its signal transduction. Here, we summarize recently identified molecular mechanisms that regulate K-Ras–PM interaction. Perturbing these mechanisms using pharmacological agents blocks K-Ras–PM binding and inhibits K-Ras signaling and growth of K-Ras–driven cancer cells. Together, these studies propose that blocking K-Ras–PM binding is a tractable strategy for developing anti–K-Ras therapies.
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Affiliation(s)
- Karen M Henkels
- Department of Biochemistry and Molecular Biology, School of Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
| | - Kristen M Rehl
- Department of Biochemistry and Molecular Biology, School of Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
| | - Kwang-Jin Cho
- Department of Biochemistry and Molecular Biology, School of Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
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Meng M, Zhong K, Jiang T, Liu Z, Kwan HY, Su T. The current understanding on the impact of KRAS on colorectal cancer. Biomed Pharmacother 2021; 140:111717. [PMID: 34044280 DOI: 10.1016/j.biopha.2021.111717] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
KRAS (kirsten rat sarcoma viral oncogene) is a member of the RAS family. KRAS mutations are one of most dominant mutations in colorectal cancer (CRC). The impact of KRAS mutations on the prognosis and survival of CRC patients drives many research studies to explore potential therapeutics or target therapy for the KRAS mutant CRC. This review summarizes the current understanding of the pathological consequences of the KRAS mutations in the development of CRC; and the impact of the mutations on the response and the sensitivity to the current front-line chemotherapy. The current therapeutic strategies for treating KRAS mutant CRC, the difficulties and challenges will also be discussed.
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Affiliation(s)
- Mingjing Meng
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Keying Zhong
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ting Jiang
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhongqiu Liu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Tao Su
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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40 Years of RAS-A Historic Overview. Genes (Basel) 2021; 12:genes12050681. [PMID: 34062774 PMCID: PMC8147265 DOI: 10.3390/genes12050681] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led to a quantitative leap in our understanding of cancer biology and set up the onset of the field of molecular oncology. The following four decades of RAS research have produced a huge pool of new knowledge about the RAS family of small GTPases, including how they regulate signaling pathways controlling many cellular physiological processes, or how oncogenic mutations trigger pathological conditions, including developmental syndromes or many cancer types. However, despite the extensive body of available basic knowledge, specific effective treatments for RAS-driven cancers are still lacking. Hopefully, recent advances involving the discovery of novel pockets on the RAS surface as well as highly specific small-molecule inhibitors able to block its interaction with effectors and/or activators may lead to the development of new, effective treatments for cancer. This review intends to provide a quick, summarized historical overview of the main milestones in RAS research spanning from the initial discovery of the viral RAS oncogenes in rodent tumors to the latest attempts at targeting RAS oncogenes in various human cancers.
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50
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Köhler J, Jänne PA. If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer. Int J Mol Sci 2021; 22:3025. [PMID: 33809660 PMCID: PMC8002337 DOI: 10.3390/ijms22063025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/26/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is "undruggable", (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically "cold" tumors into "hot" ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich's century-old "magic bullet" vision with Rudolf Virchow's cancer inflammation theory.
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Affiliation(s)
- Jens Köhler
- Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA 02215, USA
| | - Pasi A. Jänne
- Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA 02215, USA
- Belfer Center for Applied Cancer Sciences, Boston, MA 02215, USA
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