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Research ArticleSpecial Section on New Opportunities in Targeting WNT Signaling – Minireview
Open Access

Wnt Signaling and Drug Resistance in Cancer

Zheng Zhong and David M. Virshup
Molecular Pharmacology February 2020, 97 (2) 72-89; DOI: https://doi.org/10.1124/mol.119.117978
Zheng Zhong
Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
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David M. Virshup
Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
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    Fig. 1.

    Wnts are secreted proteins with conserved domains and residues. (A) The consensus modeling of 19 human Wnts. The amino acid sequences of 19 human Wnts were aligned, and the amino acid conservation scores were calculated using The ConSurf Server website (http://consurf.tau.ac.il). The conservation scores were then mapped on the human Wnt3 crystal structure (PDB 6AHY chain B). (B) The consensus modeling of Wnt homologs. The palmitoleation site and Frizzled interaction sites are conserved in all Wnts. 2635 amino acid sequences that are homologs of human Wnt3 were collected from UNIREF90 using the HMMER algorithm. The conservation scores were calculated from 150 amino acid sequences representative of the 2635 sequences using The ConSurf Server website and mapped on the human Wnt3 crystal structure. (C) The crystal structure of human Wnt3 in complex with mouse Frizzled 8 CRD (PDB 6AHY). (D) The Wnt secretion pathway. Wnts are palmitoleated by PORCN in the ER. The palmitoleic moiety (red line) facilitates the interaction of Wnts with the cargo receptor WLS that transports Wnts to the plasma membrane. Multiple routes of Wnt release and extracellular transport including diffusion, exovesicles, and cytoneme-mediated transport have been proposed.

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    Fig. 2.

    The abundance of cell surface Wnt receptors is tightly regulated by RNF43/ZNRF3, USP6, and R-Spondins. (A) RNF43 and ZNRF3 are Wnt/β-catenin target genes. (B) RNF43 and ZNRF3 ubiquitinate the cytosolic domain of Frizzleds causing the internalization and degradation of Frizzleds. (C) USP6 reverses the effects of RNF43/ZNRF3 by deubiquitinating Frizzleds. (D) R-Spondins bind to the extracellular domains of both RNF43/ZNRF3 and LGR4/5 leading to their membrane clearance. Ub, ubiquitin.

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    Fig. 3.

    The canonical Wnt/β-catenin signaling cascade. (Left panel) In the absence of Wnt ligands, β-catenin is phosphorylated, ubiquitinated, and degraded by the β-catenin destruction complex. (Right panel) Binding of Wnt ligands to the receptors relocalizes the destruction complex to the membrane and interferes with its activity. Subsequently, newly synthesized β-catenin accumulates in the cytoplasm and enters the nucleus to regulate gene transcription. Refer to the text for detailed description. DVL, dishevelled.

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    TABLE 1

    Common genetic alterations of Wnt pathway components in human cancers

    GeneType of MutationPrimary Tissues% MutatedReference
    APCMainly frameshift and nonsense mutations that lead to truncated APC proteins with compromised ability to degrade β-catenin; LOHLarge intestine70a
    Stomach13a
    Endometrium7a
    Liver2.7a
    AXIN1Mainly missense mutations, truncating mutations, and deep deletionsLiver7a
    Stomach3a
    Large intestine2.5a
    CTNNB1Mainly missense mutations in the N-terminal Ser/Thr phosphorylation sites of β-catenin that prevent its degradationLiver29a
    Endometrium18a
    Adrenal cortex16a
    Large intestine6a
    Stomach6a
    Pancreas2.7a
    RNF43Mainly missense mutations and truncating mutations due to frameshift or nonsense mutations, LOH, and homozygous deletionOvary (mucinous carcinoma/mucinous borderline tumor)21/9Ryland et al., 2013
    Stomach13a
    Biliary tract (liver fluke-associated cholangiocarcinoma)9.3Ong et al., 2012
    Large intestine9a
    Pancreas7a
    Endometrium4a
    ZNRF3Mainly missense mutations and truncating mutations due to frameshift or nonsense mutations, LOH, and homozygous deletionAdrenal cortex20a
    Large intestine4a
    Stomach2.1a
    RSPO2Chromosome rearrangement leading to the recurrent EIF3E-RSPO2 gene fusionsLarge intestine2.9Seshagiri et al., 2012
    Others (lung, head and neck, esophagus, stomach, ovary, and breast)1–2Cardona et al., 2014; Li et al., 2018
    RSPO3Chromosome rearrangement leading to the recurrent PTPRK-RSPO3 gene fusionsLarge intestine7.4Seshagiri et al., 2012
    Others (lung, head and neck, esophagus, ovary, and breast)1–11Cardona et al., 2014
    • LOH, loss of heterozygosity.

    • ↵a Curated from the cBioPortal database (https://www.cbioportal.org) in July 2019.

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    TABLE 2

    Inhibitors of the Wnt signaling and their effects in cancer

    Targets and FunctionsAgent NameFunctional Effects in CancerDevelopment StageReference
    Small molecule tankyrase (TNKS1/2) inhibitors, stabilizing AXIN1/2IWRsDiscoveryChen et al., 2009
    XAV939Inhibited colony formation of colorectal cancer cell line DLD-1.Huang et al., 2009
    WIKI4James et al., 2012
    NVP-TNKS656Shultz et al., 2013
    JW67, JW74Both compounds suppressed in vitro proliferation of colorectal cancer cell line SW480; JW74 reduced SW480 in vivo tumor growth and adenoma formation in ApcMin mice.PreclinicalWaaler et al., 2011
    JW55Suppressed in vitro proliferation of SW480; decreased adenoma formation in conditional Apc knockout mice.Waaler et al., 2012
    G007-LKSuppressed in vitro colony formation and in vivo tumor growth of colorectal cancer cell lines COLO-320DM and SW403 and spheroid formation of ApcMin mouse intestinal adenoma.Lau et al., 2013
    K-756Suppressed in vitro proliferation of COLO-320DM and SW403; showed dose-dependent inhibition of Wnt signaling in DLD-1 xenografts.Okada-Iwasaki et al., 2016
    Small molecule CK1α activators, promoting β-catenin degradationPyrviniumSuppressed in vitro proliferation of colorectal cancer cell lines SW480, DLD-1, SW620, HCT116, and HT29; reduced adenoma formation in ApcMin mice.PreclinicalThorne et al., 2010; Li et al., 2014;
    SSTC3Suppressed intestinal organoid formation from ApcMin mice and Apc knockout mice; reduced adenoma formation in ApcMin mice; suppressed in vitro colony formation of HT29, SW403, and HCT116 and in vivo tumor growth of HCT116; suppressed tumor organoid formation from three patient colorectal tumors and in vivo growth of xenografts.Li et al., 2017
    Small molecule inhibitors blocking β-catenin/TCF interactioniCRT3, iCRT5, and iCRT14iCRTs led to cell cycle arrest in HCT116 and HT29; iCRT3 suppressed in vitro growth of primary human colon cancer specimens; iCRT14 reduced HCT116 and HT29 xenograft growth.PreclinicalGonsalves et al., 2011
    Small molecule inhibitors blocking β-catenin/CBP interactionICG-001Suppressed in vitro growth and led to apoptosis in SW480 and HCT116; suppressed in vivo growth of SW620 xenografts; reduced adenoma formation in ApcMin mice; suppressed in vitro growth of pancreatic cancer cell lines AsPC-1, L3.6pl, MIA PaCa-2, and PANC-1; improved survival of AsPC-1 orthotopic xenograft-bearing mice.PreclinicalEmami et al., 2004; Arensman et al., 2014
    PRI-724The active enantiomer of ICG-001; entered Phase 1 and 2 clinical trials for treating advanced cancers.Phase 1 and 2 clinical trialsClinicalTrials.gov NCT01764477, NCT01302405, NCT01606579, NCT02413853
    Small molecule inhibitor blocking β-catenin/p300 interactionWindorphenSuppressed in vitro proliferation of colorectal cancer cell lines SW480 and RKO and prostate cancer cell lines DU145 and PC3.DiscoveryHao et al., 2013
    Small molecule PORCN inhibitors, blocking Wnt secretionIWPsDiscoveryChen et al., 2009
    C59Inhibited MMTV-Wnt1 tumor growth in vivo.PreclinicalProffitt et al., 2013
    LGK974Induced regression of MMTV-WNT1 tumors; inhibited in vitro colony formation of head and neck cancer cell line HN30 and RNF43-mutant pancreatic cancer cell lines Patu8988S and HPAF-II; inhibited in vivo tumor growth in xenografts of HN30 and RNF43-mutant pancreatic cancer cell lines Capan2 and HPAF-II; entered Phase 1 and 2 clinical trials for treating cancers.Phase 1 and 2 clinical trialsJiang et al., 2013; Liu et al., 2013; ClinicalTrials.gov NCT01351103, NCT02278133, NCT02649530
    ETC-159Inhibited in vitro colony formation of teratocarcinoma cell lines PA-1 and RNF43-mutant pancreatic and ovarian cancer cell lines HPAF-II, AsPC-1, and MCAS; suppressed in vivo tumor growth in xenografts of HPAF-II, AsPC-1, teratocarcinoma cell lines PA-1 and NCCIT, and patient-derived colorectal tumor xenografts with RSPO3 fusions; entered Phase 1 clinical trial for treating advanced cancers.Phase 1 clinical trialMadan et al., 2016a; ClinicalTrials.gov NCT02521844
    RXC004Suppressed in vivo tumor growth of Capan2 xenografts; entered Phase 1 clinical trial for treating advanced cancers.Phase 1 clinical trialBhamra et al., 2017; ClinicalTrials.gov NCT03447470
    CGX1321Suppressed in vivo tumor growth of patient-derived gastric and colorectal tumor xenografts with RSPO2 fusions; entered Phase 1 clinical trial for treating advanced cancers.Phase 1 clinical trialLi et al., 2018; ClinicalTrials.gov NCT03507998, NCT02675946
    Decoy Wnt receptorIpafricept (OMP-54F28)Suppressed in vivo tumor growth of patient-derived hepatocellular carcinoma, pancreatic and ovarian cancer xenografts, and decreased the cancer stem cell frequency; entered Phase 1 clinical trials for treating advanced cancers; in a Phase 1 clinical trial, two desmoid tumor, and a patient with germ cell cancer treated with Ipafricept experienced stable disease for >6 mo.Phase 1 clinical trialsJimeno et al., 2017; ClinicalTrials.gov NCT02069145, NCT02092363, NCT02050178, NCT01608867
    Anti-Frizzled1,2,5,7,8 antibodyVantictumab (OMP-18R5)Suppressed in vivo tumor growth of patient-derived colorectal, breast, lung, and pancreatic tumor xenografts and PA-1 xenografts; decreased the cancer stem cell frequency; entered Phase 1 clinical trials for treating cancers.Phase 1 clinical trialsGurney et al., 2012; ClinicalTrials.gov NCT01345201, NCT02005315, NCT01957007, NCT01973309
    Anti-Frizzled5,8 antibodiesIgG-2919, IgG-2921Both antibodies suppressed in vitro proliferation of RNF43-mutant pancreatic cancer cell lines HPAF-II, Patu8988S, and AsPC-1, and led to cell cycle arrest; IgG-2912 suppressed in vivo tumor growth of HPAF-II and AsPC-1 xenografts and organoid formation of RNF43-mutant colorectal cancers.PreclinicalSteinhart et al., 2017
    Anti-LRP6 antibodiesA7-IgG, B2-IgGA7-IgG specifically inhibited tumor growth of MMTV-Wnt1 xenografts; B2-IgG specifically inhibited tumor growth of MMTV-Wnt3 xenografts.PreclinicalEttenberg et al., 2010
    Anti-RSPO antibodiesAnti-RSPO1 antibody, anti-RSPO2 antibody, anti-RSPO3 antibodiesSuppressed in vivo tumor growth of patient-derived colorectal, lung, and ovarian tumor xenografts with corresponding RSPO overexpression; Anti-RSPO3 antibody (OMP-131R10) has entered Phase 1 clinical trial for treating advanced solid tumors and metastatic colorectal cancers.Preclinical, phase 1 clinical trial (OMP-131R10)Chartier et al., 2016; Storm et al., 2016; ClinicalTrials.gov NCT02482441
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    TABLE 3

    Anti-Wnt signaling-based drug combinations in cancer therapy

    Drug ADrug B (Wnt Pathway Inhibitor)Drug Combination Rationales/Preclinical ResultsClinical Trials
    Paclitaxel and carboplatin (chemo agents)Ipafricept/OMP-54F28 (decoy Wnt recptor)The drug combinations showed synergistic and potent tumor growth inhibition in patient-derived ovarian, pancreatic, hepatocellular, breast, lung, and/or colorectal cancer xenografts (Chartier et al., 2016; Fischer et al., 2017a,b; Jimeno et al., 2017).Phase 1 clinical trial (NCT02092363) in patients with recurrent platinum-sensitive ovarian cancer
    Nab-paclitaxel and gemcitabine (chemo agents)Phase 1 clinical trial (NCT02050178) in patients with previously untreated stage IV pancreatic cancer
    Sorafenib (RAF, VEGFR, and PDGFR inhibitor)Phase 1 clinical trial (NCT02069145) in patients with hepatocellular cancer
    Paclitaxel (chemo agent)Vantictumab/OMP-18R5 (anti-Frizzleds antibody)Phase 1 clinical trial (NCT01973309) in patients with locally recurrent or metastatic breast cancer
    Docetaxel (chemo agents)Phase 1 clinical trial (NCT01957007) in patients with previously treated non-small-cell lung carcinoma
    Nab-paclitaxel and gemcitabine (chemo agents)Phase 1 clinical trial (NCT02005315) in patients with previously untreated stage IV pancreatic cancer
    Taxol, gemcitabine, or irinotecan (chemo agents)Anti-RSPO1, anti-RSPO2, and anti-RSPO3 antibodies
    FOLFIRI (chemo agents)OMP-131R10 (anti-RSPO3 antibody)Phase 1 clinical trial (NCT02482441) in patients with metastatic colorectal cancer
    API2 (AKT inhibitor)NVP-TNKS656 (tankyrase inhibitor)Tankyrase inhibition reverted resistance to AKT inhibition in patient-derived colorectal cancer xenografts (Arques et al., 2016).
    Gefitinib or AZD9291 (EGFR inhibitors)AZ1366 (tankyrase inhibitor)The drug combination significantly slowed down growth of non–small cell lung cancer orthotopic xenografts and improved survival of tumor-bearing mice (Scarborough et al., 2017).
    Vemurafenib (BRAF inhibitor)ICG-001 (blocking β-catenin/TCF interaction)BRAF inhibition upregulated β-catenin signaling in colorectal cancer cell lines in vitro. The drug combination led to synergistic tumor growth inhibition in HT29 xenografts (Chen et al., 2018).
    LGX818 (BRAF inhibitor) and Cetuximab (EGFR inhibitor)LGK974 (PORCN inhibitor)A subset of colorectal cancers harbor concurrent mutations in BRAF and RNF43 or RSPOs (Yan et al., 2017).Phase 1/2 clinical trial (NCT02278133) in patients with BRAF-mutant metastatic colorectal cancer with Wnt pathway mutations
    Buparlisib/BKM120 (pan-PI3K inhibitor)LGK974 (PORCN inhibitor)Burparlisib treatment upregulated Wnt signaling in triple negative breast cancer (TNBC) cell lines in vitro. The drug combination led to synergistic tumor growth inhibition in xenografts of TNBC cell line TMD231 (Solzak et al., 2017).
    Multiple PI3K/mTOR inhibitors including GDC-0941, ZSTK474, LY-294002, AS252424, and Ku0063794ETC-159 (PORCN inhibitor)ETC-159 in combination with one of the five PI3K/mTOR inhibitors synergistically suppressed 3D colony formation of several Wnt-addicted pancreatic and cholangiocarcinoma cell lines. ETC-159 in combination with GDC-0941 led to synergistic tumor growth inhibition in HPAF-II and AsPC-1 xenografts (Zhong et al., 2019).
    Olaparib (PARP inhibitor)Pyrvinium (CK1α activator) or XAV939 (tankyrase inhibitor)Wnt/β-catenin signaling mediated resistance to PARP inhibition in ovarian cancer due in part to upregulation of DNA damage repair. Inhibition of β-catenin signaling reverted resistance to olaparib in ovarian cancer xenografts (Fukumoto et al., 2019; Yamamoto et al., 2019).
    Vismodegib (Hedgehog signaling inhibitor)LGK974 (PORCN inhibitor) or anti-LRP6 antibodyA LGR5+ tumor cell population maintained by active Wnt signaling persists vismodegib treatment in human and mouse basal cell carcinoma and mediates relapse after treatment discontinuation. The drug combination reduced tumor burden (vismodegib + anti-LRP6 antibody) or eliminated resistant tumor cells (vismodegib + LGK974) in mouse models (Biehs et al., 2018; SanchezDanes et al., 2018).
    PDR001 (anti-PD1 antibody)LGK974 (PORCN inhibitor)Preclinical studies showed that Wnt signaling mediated resistance to immunotherapies, and concurrent inhibition of Wnt/β-catenin signaling enhanced the efficacy of immune checkpoint inhibitors in melanoma mouse models (Holtzhausen et al., 2015; Spranger et al., 2015; Zhao et al., 2018).Phase 1 clinical trial (NCT01351103) in patients with malignancies dependent on Wnt ligands
    Pembrolizumab (anti-PD1 antibody)ETC-159 (PORCN inhibitor)Phase 1 clinical trial (NCT02521844) in patients with advanced solid tumor
    CGX1321 (PORCN inhibitor)Phase 1 clinical trial (NCT02675946) in patients with advanced gastrointestinal tumor

Additional Files

  • Figures
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  • Data Supplement

    • Supplemental Data -

      Supplementary Data 

    • Supplemental Data -

      Supplementary Data - PDB 6ahy 19seq

    • Supplemental Data -

      Supplementary Data - PY 6ahy 19seq


    • Supplemental Data -

      Supplementary Data - PDB 6ahy Global


    • Supplemental Data -

      Supplementary Data - PY 6ahy Global


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Molecular Pharmacology: 97 (2)
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1 Feb 2020
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Research ArticleSpecial Section on New Opportunities in Targeting WNT Signaling – Minireview

Wnt Signaling and Drug Resistance in Cancer

Zheng Zhong and David M. Virshup
Molecular Pharmacology February 1, 2020, 97 (2) 72-89; DOI: https://doi.org/10.1124/mol.119.117978

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Research ArticleSpecial Section on New Opportunities in Targeting WNT Signaling – Minireview

Wnt Signaling and Drug Resistance in Cancer

Zheng Zhong and David M. Virshup
Molecular Pharmacology February 1, 2020, 97 (2) 72-89; DOI: https://doi.org/10.1124/mol.119.117978
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  • Article
    • Abstract
    • Introduction
    • Wnt Signaling Pathway
    • Aberrant Wnt Signaling in Cancer and Pharmacological Targeting of Wnt Signaling
    • Wnt Signaling Mediated Resistance in Cancer Therapy
    • Resistance to Wnt Pathway Blockade in Normal Tissue and Wnt-Driven Cancer
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  • Class F Receptors as Molecular Machines
  • WNT Signaling in Cardiomyocyte Proliferation
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