ArticleThe Journal of clinical investigation2024
Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.
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Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19citing papers in PubMed
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Who cites it
19 citing papers in PubMed.
- Discovery of a novel and potent KRASJournal of enzyme inhibition and medicinal chemistry · 2026Article
- Mechanisms, regulation and clinical relevance of necroptosis.Nature reviews. Molecular cell biology · 2026Review
- Targeted KRASG12V Degradation In Vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis.Cancer research · 2026Article
- Targeting the non-coding RNA-PANoptosis axis: a novel frontier in disease diagnosis and therapy.Apoptosis : an international journal on programmed cell death · 2026Review
- A Versatile Multiplexed Immunofluorescence Strategy for Efficient, Host-Independent, and Scalable Spatial Protein Profiling.Small methods · 2026Article
- The benchmarking and application of tag-degraders in vivo to validate therapeutic targets.Nature communications · 2026Article
- Development of PROTACs for targeted degradation of oncogenic TRK fusions.RSC chemical biology · 2026Article
- Degron models: a toolbox for rapid in vivo depletion of essential proteins regulating mRNA metabolism.Communications biology · 2026Article
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- Synuclein Proteoforms: Role in Health and Disease.Molecular neurobiology · 2025Review
- Antibiotic administration decreases microglia and macrophage recruitment in a sex-dependent manner following Degenerative Cervical Myelopathy.Molecular neurobiology · 2025Article
- A first-in-class EGFR-directed KRAS G12V selective inhibitor.Cancer cell · 2025Article
- Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs.Molecular cancer · 2025Review
- Review
- Review
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
- SARS-CoV-2 N protein exerts antitumor effects in NSCLC by inducing DNA damage and augmenting chemotherapeutic sensitivity.Medical oncology (Northwood, London, England) · 2025Article
- Review
- Impact of MEK inhibition on T-cell infiltration and function after radiotherapy in KRAS-mutant lung cancer.Frontiers in immunology · 2025Article
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Authors and funding
43 authors.
Dezhi LiDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Ke GengDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Yuan HaoApplied Bioinformatics Laboratories, Office of Science and Research, New York University Grossman School of Medicine, New York, New York, USA.
Jiajia GuHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Saurav KumarHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Annabel T OlsonHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Christina C KuismiHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Hye Mi KimHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Yuanwang PanDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Fiona ShermanDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Asia M WilliamsHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Yiting LiHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Fei LiDepartment of Pathology, School of Basic Medical Sciences, and.
Ting ChenDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Cassandra ThakurdinDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Michela RanieriDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Mary MeynardieDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Daniel S LevinDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Janaye StephensDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Alison ChafitzDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Joy ChenHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Mia S Donald-PaladinoHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Jaylen M PowellDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Ze-Yan ZhangDepartment of Radiation Oncology, New York University Grossman School of Medicine, New York, New York, USA.
Wei ChenDivision of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Magdalena PloszajDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Han HanDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Shengqing Stan GuDepartment of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Tinghu ZhangDepartment of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Baoli HuHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Benjamin A NacevHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Medard Ernest KaizaHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Alice H BergerHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Xuerui WangHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Jing LiHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Xuejiao SunHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Yang LiuDepartment of Bioengineering, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
Xiaoyang ZhangDepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Tullia C BrunoHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Nathanael S GrayDepartment of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Behnam NabetHuman Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Kwok-Kin WongDivision of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
Hua ZhangHillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
Funding
Translational Bioimaging Core Shared ResourceP30CA015704 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Eric Collisson · 1985 to 2026
$296.4MVECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHRISTOPHER J. BAKKENIST · 1988 to 2026
$158.0MVaccine FacilityP30CA016087 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI MARK Reid PHILIPS · 1985 to 2026
$83.1MTR&D 4: Revealing Microstructure: Biophysical modeling and validation for discovery and clinical careP41EB017183 · NIBIB · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Daniel K Sodickson · 2014 to 2026
$19.3MDiseases of Public Health Importance Training GrantT32AI007509 · NIAID · UNIVERSITY OF WASHINGTON · PI LUND, JENNIFER M · 1997 to 2024
$6.3MA Patient-Centric Approach to Advance Functional Precision OncologyU01CA282109 · NCI · FRED HUTCHINSON CANCER CENTER · PI CHRISTOPHER J KEMP · 2023 to 2026
$4.2MUnderstanding and exploiting novel therapeutic vulnerabilities of RIT1-driven lung cancerR37CA252050 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Alice Berger · 2021 to 2026
$3.1MImaging nanoscale chromatin folding in early carcinogenesisR01CA254112 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI LIU, YANG · 2020 to 2025
$2.2MComputational and functional discovery of isoforms driving cancer and drug resistanceR01CA284585 · NCI · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI Alice Berger, Angela Norie Brooks · 2024 to 2026
$2.1MExpanding the cancer paralog genetic interaction map to enable precision oncologyR01CA262556 · NCI · FRED HUTCHINSON CANCER CENTER · PI Alice Berger · 2024 to 2026
$1.6MTargeted disruption of the YAP/TAZ/TEAD axis in pancreatic cancerK22CA258805 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI NABET, BEHNAM · 2021 to 2024
$644kEnhancing the efficacy of immunotherapy by optimal use of SMAC mimeticsK22CA279077 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Shengqing Gu · 2024 to 2026
$577kNCI NIH HHS K22 CA258805NCI NIH HHS K22 CA276357NCI NIH HHS K22 CA279077NCI NIH HHS P30 CA015704NCI NIH HHS P30 CA016087NCI NIH HHS P30 CA047904NCI NIH HHS R01 CA254112NCI NIH HHS R01 CA262556NCI NIH HHS R01 CA284585NCI NIH HHS R37 CA252050NCI NIH HHS U01 CA282109NIAID NIH HHS T32 AI007509NIBIB NIH HHS P41 EB017183
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers.
Indexed as
Lung NeoplasmsMutation, MissenseProteolysisProto-Oncogene Proteins p21(ras)Tumor MicroenvironmentAdenocarcinoma of LungAnimalsCD8-Positive T-LymphocytesDisease Models, AnimalHumansMiceMice, TransgenicHras protein, mouseKRAS protein, humanProto-Oncogene Proteins p21(ras)ImmunologyLung cancerOncology
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.