ArticleMolecular cell2020
Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma.
Erratum issuedOpen access · bronzeAbstract read
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Article in Molecular cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 46 papers.
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46citing papers in PubMed
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Who cites it
46 citing papers in PubMed, 81 citations in OpenAlex.
- The p53 Isoforms as Potential Biomarkers in Different Cancer Entities.International journal of molecular sciences · 2026Review
- Scalable longitudinal imaging and transcriptomics of cells in dynamic enclosures.bioRxiv : the preprint server for biology · 2026Article
- Identification and characterization of BRAF⇔TP53 interactions in melanoma.Cell reports · 2026Article
- Regulation of doxorubicin resistance and cellular metabolism by miR-203a-3p via p53 and TAp63 signaling in hepatocellular carcinoma.Frontiers in pharmacology · 2026Article
- Melanoma: Pathogenesis and Targeted Therapy.MedComm · 2026Review
- Advances in cold atmospheric plasma therapy for cancer.Bioactive materials · 2025Review
- Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma.Nature communications · 2024Article
- The crosstalk of Wnt/β-catenin signaling and p53 in acute kidney injury and chronic kidney disease.Kidney research and clinical practice · 2024Article
- Article
- Determinants of resistance and response to melanoma therapy.Nature cancer · 2024Review
- Article
- The Pathology according to p53 Pathway.Pathobiology : journal of immunopathology, molecular and cellular biology · 2024Review
- Review
- Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor.Disease models & mechanisms · 2023Article
- An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.Cancer discovery · 2023Article
- Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat).International journal of molecular sciences · 2023Article
- The Roles of Secreted Wnt Ligands in Cancer.International journal of molecular sciences · 2023Review
- Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.Cancer discovery · 2023Article
- FBXW7 attenuates tumor drug resistance and enhances the efficacy of immunotherapy.Frontiers in oncology · 2023Review
- PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma.Cell communication and signaling : CCS · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
32 authors at 8 institutions in 2 countries.
Marie R WebsterImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA. Electronic address: websterm@mlhs.org.
Mitchell E FaneImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Gretchen M AliceaImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; University of the Sciences, Philadelphia, PA 19104, USA.
Subhasree BasuMolecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.
Andrew V KossenkovBioinformatics, The Wistar Institute, Philadelphia, PA 19104, USA.
Gloria E MarinoImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Stephen M DouglassImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Amanpreet KaurImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; University of the Sciences, Philadelphia, PA 19104, USA.
Brett L EckerImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Department of Surgery, University of Pennsylvania Hospital, Philadelphia, PA 19104, USA.
Keerthana GnanapradeepanMolecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Abibatou NdoyeImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; University of the Sciences, Philadelphia, PA 19104, USA.
Curtis KugelImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Alexander ValigaImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Jessica PalmerImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Qin LiuMolecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.
Xiaowei XuAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jessicamarie MorrisImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Xiangfan YinMolecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.
Hong WuFox Chase Cancer Center, Philadelphia, PA 19111, USA.
Wei XuAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cathy ZhengAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Giorgos C KarakousisAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ravi K AmaravadiAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Tara C MitchellAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Filipe V AlmeidaImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Min XiaoImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Vito W RebeccaImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Ying-Jie WangState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310003, China.
Lynn M SchuchterAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center at Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Meenhard HerlynImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.
Maureen E MurphyMolecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.
Ashani T WeeraratnaImmunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: aweerara1@jhu.edu.
University of Pennsylvania · USThe Wistar Institute · USUniversity of the Sciences · USFox Chase Cancer Center · USJohns Hopkins University · USLankenau Institute for Medical Research · USPennsylvania Hospital · USZhejiang University · CN
Funding
Translational Research Central ServicesP30CA006973 · NCI · JOHNS HOPKINS UNIVERSITY · PI Rosalie Wollett · 1985 to 2026
$208.6MTumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Luis J Montaner · 1985 to 2026
$75.9MTargeting the MAP and PI3 Kinase Pathways in MelanomaP01CA114046 · NCI · WISTAR INSTITUTE · PI WEERARATNA, ASHANI T · 2008 to 2023
$37.1MTargeted Combination Therapy for MelanomaP50CA174523 · NCI · WISTAR INSTITUTE · PI HERLYN, MEENHARD F · 2014 to 2018
$11.1MFunctional Analysis of p53 Polymorphic Variants - Diversity SupplementR01CA102184 · NCI · WISTAR INSTITUTE · PI Maureen E. Murphy · 2005 to 2026
$7.4MA plasticity and reprogramming paradigm for therapy resistance at the single cell levelU01CA227550 · NCI · UNIVERSITY OF PENNSYLVANIA · PI RADHAKRISHNAN, RAVI, RAJ, ARJUN · 2018 to 2022
$3.3MAn integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skinR01CA232256 · NCI · WISTAR INSTITUTE · PI CUKIERMAN, EDNA, RAJ, ARJUN · 2019 to 2023
$3.0MPromotion of tumor invasion and pseudosenescence by the aging microenvironmentR01CA174746 · NCI · WISTAR INSTITUTE · PI WEERARATNA, ASHANI T · 2014 to 2018
$2.1MEffect of the aged microenvironment on tumor dormancyR01CA207935 · NCI · WISTAR INSTITUTE · PI WEERARATNA, ASHANI T · 2017 to 2021
$2.0MIntegrative Approach to Comprehensive Analysis of High Throughput Data on a Cancer Center LevelR50CA211199 · NCI · WISTAR INSTITUTE · PI Andrew V Kossenkov · 2016 to 2026
$1.6MHistone modifications regulating phenotype plasticity: Role of non-canonical Wnt signalingK99CA208012 · NCI · WISTAR INSTITUTE · PI WEBSTER, MARIE RUTH · 2016 to 2017
$228kNCI NIH HHS K99 CA208012NCI NIH HHS P01 CA114046NCI NIH HHS P30 CA006973NCI NIH HHS P30 CA010815NCI NIH HHS P50 CA174523NCI NIH HHS R01 CA102184NCI NIH HHS R01 CA174746NCI NIH HHS R01 CA207935NCI NIH HHS R01 CA232256NCI NIH HHS R50 CA211199NCI NIH HHS U01 CA227550
Abstract
Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.
Indexed as
Cell Line, TumorDrug Resistance, NeoplasmHumansMAP Kinase Kinase KinasesMelanomaMolecular Targeted TherapyMutationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSignal TransductionSulfonamidesTumor MicroenvironmentTumor Suppressor Protein p53Wnt-5a ProteinBRAF protein, humanMAP Kinase Kinase KinasesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSulfonamidesTumor Suppressor Protein p53Wnt-5a ProteinWNT5A protein, humanaged microenvironmentmelanomaslow-cycling phenotypetherapy resistancetumor microenvironmentwild-type 53Wnt5A
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