Targeting The Wnt/β-catenin Signaling Pathway In Cancer
(2020) 13:165Zhang and Wang J Hematol n AccessREVIEWTargeting the Wnt/β‑catenin signalingpathway in cancerYa Zhang1,2,3,4,5,6 and Xin Wang1,2,3,4,5,6*AbstractThe aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight thetherapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenindestruction complex and TCF/β-catenin transcription complex are key components of the cascade and have beentargeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latestprogress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-cateninpathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted toconfirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.Keywords: Wnt/β-catenin signaling pathway, Cancer, Targeted therapy, Cancer stem cellIntroductionThe Wnt/β-catenin signaling pathway, also called thecanonical Wnt signaling pathway, is a conserved signalingaxis participating in diverse physiological processes suchas proliferation, differentiation, apoptosis, migration,invasion and tissue homeostasis [1–3]. Increasing evidence indicates that dysregulation of the Wnt/β-catenincascade contributed to the development and progressionof some solid tumors and hematological malignancies[4–8].In the Wnt/β-catenin pathway, abnormal regulationof the transcription factor β-catenin, which is the pivotal component of the Wnt signaling pathway, leads toearly events in carcinogenesis [9–12]. Within the degradation complex, glycogen synthase kinase 3β (GSK3β)and casein kinase 1α (CK1α) mediate the phosphorylation of β-catenin, promoting its ubiquitinationand subsequent proteasomal degradation [13, 14]. The*Correspondence: xinw007@126.com; xinw@sdu.edu.cn1Department of Hematology, Shandong Provincial Hospital Affiliatedto Shandong First Medical University, Jinan 250021, Shandong, ChinaFull list of author information is available at the end of the articleβ-catenin-dependent signaling pathway is triggered bythe binding of secreted cysteine-rich glycoprotein ligandsWnts to the LRP-5/6 receptors and FZD receptors. In thepresence of Wnt ligand, the binding of Wnt ligand andreceptors on the cell surface induces disheveled (DVL),causing the aggregation of the complex (AXIN, GSK3β,CK1, APC) to the receptor [15]. Subsequently, the phosphorylation and inhibition of GSK3β ensure an elevationof cytosolic β-catenin concentration. Un-phosphorylatedβ-catenin in the cytosol migrates to the nucleus andaccumulates, interacting with T cell-specific factor(TCF)/lymphoid enhancer-binding factor (LEF) and coactivators, such as Pygopus and Bcl-9, to trigger the Wnttarget genes like c-Myc, cyclin D1 and CDKN1A, resulting in the upregulation of TCF/LEF target gene.In addition, multiple regulatory mechanisms have beenidentified on the phosphorylation and ubiquitination ofβ-catenin by the degradation complex. Notum, whichremoves palmitoleate from Wnt proteins, blocks theirextracellular secretion. Dickkopf (DKK) negatively regulates the initiation of Wnt protein-mediated signalingby competitively binding to LRP5/6 receptors. Besides,secreted FZD-related proteins (sFRPs), which bind to The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whichpermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit lineto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Zhang and Wang J Hematol Oncol(2020) 13:165FZD receptors also blocking the initiation of Wnt protein-mediated signaling. Moreover, Wnt inhibitory factor (WIF) inhibits signaling by binding directly to Wntproteins [16]. The transmembrane molecules ZNRF3 andRNF43 act on FZD molecules with E3 ubiquitin ligaseactivity [14, 17]. The 7-transmembrane receptor LGR4,LGR5 and LGR6 bind to R-spondins (RSPO) with highaffinity to enhance the Wnt signal at a low dose of Wntligand [14, 18]. To elucidate the mechanism of Wnt/βcatenin signaling pathway activation and inhibition, aschematic diagram was depicted in Fig. 1.Furthermore, Wnt/β-catenin signaling orchestratesmultiple cell signaling cascades, such as epidermalPage 2 of 16growth factor receptor (EGFR), Hippo/YAP, nuclearfactor kappa-B (NF-κB), Notch, Sonic Hedgehog andPI3K/Akt pathway, which contribute to pivotal molecular mechanism in cancer development [19–24]. EGFRcould form a complex with β-catenin and promotes theinvasion and metastasis of cancer cells [25, 26]. Moreover, the Hippo pathway has been shown to inhibit Dvlphosphorylation, nuclear accumulation of β-cateninand transcription of β-catenin/TCF-target genes in theWnt/β-catenin signaling [21, 27]. Besides, the activation of Wnt/β-catenin pathway interacted with PI3K/AKT/GSK-3 cascade in glioblastoma cells and furtherprovided mechanistic basis for the chemoresistance toFig. 1 Schematic representation of activated and inhibited Wnt/β-catenin pathway. “WNT ON state”: Upon ligation of Wnts to their receptorscomposed of frizzled proteins and LRP5/6, the cytoplasmic protein DVL is activated and induces the suppression of GSK3β. Subsequently, stabilizedβ-catenin translocates into the nucleus and binds to TCF/LEF transcription factors to lead to target gene transcription. “WNT OFF state”: In theabsence of WNT ligand, the destruction complex of β-catenin, a tertiary complex formed by AXIN, CK1α, GSK3β and APC, phosphorylates β-catenin,which subsequently undergoes the ubiquitin-proteasomal degradation
Zhang and Wang J Hematol Oncol(2020) 13:165Page 3 of 16temozolomide [22]. Additionally, AKT kinase could alsoactivate β-catenin. Therefore, the cross talk betweenWnt/β-catenin and PI3K-AKT pathway was confirmed topromote tumorigenesis and resistance to cancer therapy[23, 28].Collectively, underscoring the physiological importance of Wnt/β-catenin signaling pathway in tumorigenesis, targeted agents are explored and presentedpromising therapeutic potential in preclinical studiesand clinical trials of some cancer types. In the presentreview, we elaborated on the advances and challenges ofWnt/β-catenin signaling pathway targeted interventionsin malignancies, aiming to provide rationales and insightson novel strategies in cancer therapy.an EOC mouse model, treatment with CGX1321 led toprolonged overall survival, decreased tumor burden andincreased immune cell infiltration. Furthermore, effectsof some other PORCN inhibitors were evaluated in preclinical studies [34, 35]. It was reported that the combination of the PORCN inhibitor ETC-159 and the PI3Kinhibitor GDC-0941 decreased RNF43-mutant pancreatic cancer cell proliferation and xenograft growth in vivo[36]. Besides, IWP-O1 was observed with significantlyimproved metabolic stability and inhibit the phosphorylation of DVL in Hela cells [37]. Moreover, GNF-6231demonstrated potent inhibition activities and inducedrobust anti-tumor efficacy in a breast cancer mousemodel [38].Wnt/β‑catenin signaling pathway interventions for cancerWnt/FZD antagonistsThe deregulation of Wnt/β-catenin signaling pathway isclosely related to the initiation and progression of various types of cancers [4, 5, 29]. Thus, inhibitors, antagonists and agonists were designed to target this cascadein solid tumors (Table 1) and hematological malignancies (Table 2). Formulas and structures of agents targetedWnt/β-catenin signaling pathway are listed in Additionalfile 1. Hallmarks of diverse categories of Wnt/β-catenintargeted agents in malignancies are illustrated in Fig. 2.In addition, Fig. 3 is plotted to present a panoramic overview of Wnt/β-catenin signaling pathway targeted interventions in cancer therapy, which was deciphered in thefollowing aspects.With the antagonism of Wnt ligands and FZD receptors, canonical Wnt signaling pathway was suppressedand indicated potential strategy in cancer therapy. Ipafricept (OMP54F28; IPA) is a recombinant fusion protein, including the cysteine-rich domain of FZD8 fusedto a human IgG1 Fc fragment [39]. This structure couldbind directly to Wnt ligands, competing for the bindingof Wnt ligands with FZD8 receptor, thereby inhibitingWnt regulated processes [40]. In patient-derived ovarian cancer xenograft mice models, ipafricept displayedactivity to decrease the population of stem cells, suppresstumor development and promote differentiation. In addition, in preclinical studies, ipafricept exhibits synergisticanti-tumor effects combined with taxanes when givenprior to chemotherapy two to three days, with 82% ofthe patients achieved a partial or complete response [41].Ipafricept was also investigated in a phase 1b dose-escalation study in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovariancancer. The combination of these three agents producedsimilar response rates and survival outcomes comparedwith historical treatment regimens. Nevertheless, bonetoxicities at efficacy doses prevented further testing ofthis treatment regimen. A phase 1b clinical trials suggested that ipafricept could also be administered withnab-paclitaxel and gemcitabine with reasonable tolerancein patients with previously untreated stage IV pancreaticcancer [42].OMP-18R5 (vantictumab) is a monoclonal antibodytargeting FZD1, FZD2, FZD5, FZD7 and FZD8 [43–45].OMP-18R5 blocks tumor growth in xenograft mousemodels of breast, pancreatic, colon, lung, and headand neck cancers and is being evaluated in a number ofphase I trials for these tumor types [43, 46]. In a clinical trial, OTSA-101 was demonstrated that radioimmunotherapy targeting FZD10 is feasible in synovialsarcoma patients [47]. Besides, Pavlovic et al. utilizedInhibitors targeting Wnt ligand/ receptor interfacePorcupine inhibitorsPorcupine (PORCN), a family member of membranebound O-acyltransferases (MBOAT), is key for the secretion of Wnt ligands [30, 31]. Several inhibitors that targetPORCN prevent the palmitoylation of Wnt proteins inthe endoplasmic reticulum, which subsequently prevents their secretion [13, 24]. Blocking the acylation ofWNT with a PORCN inhibitor to abolish WNT secretion becomes an effective treatment strategy. WNT974(LGK974) is an orally available small molecule inhibitor that decreases epithelial ovarian cancer (EOC) cellviability in vitro and inhibits tumor growth in vivo [24,32]. In EOC preclinical mouse models, WNT974 presents enhanced anti-tumor effects with the combinationof paclitaxel [33]. There is currently a phase I clinicaltrial investigating WNT974 monotherapy for patientswith pancreatic cancer, triple-negative breast cancerand cervical squamous cell carcinoma (NCT01351103).CGX1321, another PORCN inhibitor, inhibits bothcanonical and non-canonical Wnt signaling pathways.The single-dose escalation of CGX1321 is invested in aphase 1 clinical trial (NCT02675946) in solid tumors. In
Zhang and Wang J Hematol Oncol(2020) 13:165Page 4 of 16Table 1 Clinical trials and preclinical evaluations on Wnt/β-catenin targeted agents in solid tumorsAgentsMechanismPhaseCancer typeSide effectsIdentifierWNT974PORCN inhibitorPhase 2Head and neck squamouscell cancerNRNCT02649530WNT974PORCN inhibitorPhase 1Pancreatic cancer; colorectal NRcancer; melanoma; breastcancer; head and necksquamous cell cancer; cervical squamous cell cancer;esophageal squamous cellcancer; lung squamous cellcancerNCT01351103*WNT974 (with LGX818 andCetuximab)PORCN inhibitorPhase 1Colorectal cancerNRNCT02278133ETC-159PORCN inhibitorPhase 1Solid tumorReversible hematologicaldisordersNCT02521844CGX1321PORCN inhibitorPhase 1Colorectal adenocarcinoma; NRgastric adenocarcinoma;pancreatic adenocarcinoma; bile duct carcinoma;hepatocellular carcinoma,esophageal carcinoma,Gastrointestinal cancerNCT03507998*CGX1321 (with pembrolizumab)PORCN inhibitorPhase 1Solid tumors; Gastrointestinal NRcancerNCT02675946GNF-6231PORCN inhibitorPreclinical Breast cancerNR–90FZD10 antagonistPhase 1Synovial sarcomaNRNCT01469975OMP-18R5Monoclonal antibodyagainst FZD receptorsPhase 1Breast cancerNausea, alopecia, fatigue,peripheral neuropathyNCT01973309OMP-18R5Monoclonal antibodyagainst FZD receptorsPhase 1Solid tumorsNRNCT01345201*OMP-18R5 (with docetaxel)Monoclonal antibodyagainst FZD receptorsPhase 1Solid tumorsNRNCT01957007*OMP-18R5 (with nab-paclitaxel and gemcitabine)Monoclonal antibodyagainst FZD receptorsPhase 1Pancreatic cancerNRNCT02005315OMP-54F28FZD8 decoy receptorPhase 1Solid tumorsDysgeusia, muscle spasms,hypophosphatemiaNCT01608867*OMP-54F28 (with sorafenib)FZD8 decoy receptorPhase 1Hepatocellular cancerDiarrhea, neutropenia anddecreased appetiteNCT02069145*OMP-54F28 (with paclitaxeland carboplatin)FZD8 decoy receptorPhase 1Ovarian cancerNRNCT02092363*OMP-54F28 (with nab-pacli- FZD8 decoy receptortaxel and gemcitabine)Phase 1Pancreatic cancerNRNCT02050178Fz7-21FZD7 antagonistPreclinical Gastroenteric tumor––SalinomycinLRP5/6 inhibitorPreclinical Hepatocellular carcinoma;gastric cancer; colorectalcancer; bladder cancer;breast cancer––FJ9DVL inhibitorPreclinical Lung cancer; melanoma––3289–8625DVL inhibitorPreclinical Ovarian cancer; lung cancer––XAV939Tankyrase inhibitorPreclinical Ovarian cancer; breastcancer––JW74/ JW55Tankyrase inhibitorPreclinical Osteosarcoma, colon carcinoma––NVP-TNKS656Tankyrase inhibitorPreclinical Hepatocellular carcinoma;colorectal cancer––LZZ-02Tankyrase inhibitorPreclinical Colonic carcinoma––SSTC3CK1α activatorPreclinical Colorectal cancer––LF3β-catenin/TCFPreclinical Colon cancer––γ-OTSA-101
Zhang and Wang J Hematol Oncol(2020) 13:165Page 5 of 16Table 1 (continued)AgentsMechanismPhaseKYA1797K/ KY1220β-cateniniCRT3/5ZINC02092166Cancer typeSide effectsIdentifierPreclinical Colorectal cancer, breastcancer––β-catenin/TCFPreclinical Breast cancer; gastric cancer––β-catenin/TCFPreclinical Colorectal cancer––NLS-StAx-hβ-catenin/TCFPreclinical Colorectal cancer––*PRI-724 (with leucovorincalcium, oxaliplatin, orfluorouracil)CBP/β-catenin antagonistPhase 2Colorectal cancerNausea, fatigueNCT02413853PRI-724CBP/β-catenin antagonistPhase 1Pancreatic cancerNRNCT01764477PRI-724CBP/β-catenin antagonistPhase 1Advanced solid tumorsNausea, vomiting, diarrhea,alopecia, fatigue, neutropenia, thrombocytopenia,neutropenic feverNCT01302405ICG001CBP antagonistPreclinical Pancreatic cancer, lung cancer, breast cancer; ovariancancer––IsoquercitrinCBP antagonistPreclinical Colorectal cancer––Table 2 Clinical trials and preclinical evaluations on Wnt/β-catenin targeted agents in hematological malignanciesAgentsMechanismPhaseCancer typeSide effectsIdentifierCWP291SAM68 inhibitorPhase 1Relapsed or refractoryAML and MDSNausea, vomiting, diarrhea, andinfusion-related reactionsNCT01398462PRI-724CBP/β-catenin antagonistPhase 2AML; CMLNRNCT01606579GNE-781CBP antagonistPreclinicalAML––ICG001CBP antagonistPreclinicalAML; ALL; CML; MM––WNT974PORCN inhibitorPreclinicalBL–Wnt-C59PORCN inhibitorPreclinicalcHL–IWP-2/IWP-4PORCN inhibitorPreclinicalAML; cHL–XAV939Tankyrase inhibitorPreclinicalAML; T-ALL; CML–IWR-1Tankyrase inhibitorPreclinicalAPL–SalinomycinLRP5/6 inhibitorPreclinicalCLL; MCL–iCRT14β-catenin/TCFPreclinicalALL; MCL–Fig. 2 Hallmarks of diverse categories of Wnt/β-catenin targeted agents in cancer
Zhang and Wang J Hematol Oncol(2020) 13:165Page 6 of 16Fig. 3 Graphic overview of Wnt/β-catenin signaling pathway targeted interventions in cancer studies. Promising therapeutics targeting Wnt ligand/receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are investigated in preclinical and clinical evaluationscombinatorial antibody engineering by phage displayto generate a variant antibody F2.A with specificity ofFZD4 [44]. F2.A suppresses pancreatic cancer tumorgrowth in xenograft mouse models. Interestingly,carbamazepine, an antiepileptic drug, was recentlyreported to bind the cysteine-rich domain of FZD8,which suggests been explored as a promising therapyoption in cancers [48]. Additionally, Fz7-21, a selectiveFZD7-binding peptide, disrupts intestinal stem cellsand organoids, implicating the potential of therapeuticapplication in malignant diseases [49].LRP5/6 inhibitorsAs the co-receptor of Wnt, the phosphorylation ofLRP5/6 promotes the activation of Wnt/β-cateninsignaling pathway. The molecular complex Wnt-FZDLRP5/6-DVL forms a structural region for AXINinteraction that disrupts degradation of β-catenin.BMD4503-2, a quinoxaline moiety, was identified asa new small-molecule inhibitor of the LRP5/6-sclerostin interaction through pharmacophore-basedvirtual screening and in vitro assays. The compoundBMD4503-2 could revert the down-regulated activity of the Wnt/β-catenin signaling pathway through
Zhang and Wang J Hematol Oncol(2020) 13:165competitively binding to the LRP5/6-sclerostin complex [50].DVL inhibitorsDVL is important for Wnt signal transduction byrecruiting components of the β-catenin destructioncomplex to the cell membrane [51, 52]. DVL binds tothe cytoplasmic carboxyl terminal end of FZD proteinsthrough its PDZ domain [53]. NSC668036, FJ9, and3289–8625 are some agents that block the DVL-PDZinteraction, resulting in subsequently inhibition of thesignal transduction pathway [54, 55]. The non-electrophilic indole-2-carbinol-based chemical scaffold of FJ9disrupted the interaction between FZD and the PDZdomain of DVL. NSC668036 and 3289–8625 were confirmed to down-regulate Wnt/β-catenin signaling andinhibit tumor cell growth in lung, colorectal and cervical cancer cell lines in vitro, as well as in a lung cancerxenografts [54].Agents targeting the β‑catenin‑destruction complexTankyrase inhibitorsScaffolding protein AXIN is the rate-limiting component of the β-catenin destruction complex, whichare constantly surveyed and regulated by tankyrases[56–58]. Tankyrases belong to the Poly (ADP-ribose)polymerases (PARPs) family, regulating the stability ofAXIN1 and AXIN2 through directing AXIN ubiquitylation by RNF146 and proteasomal degradation [59,60]. There are two isoforms, Tankyrase 1 (PARP5a) andTankyrase 2 (PARP5b) involved in the Wnt/β-cateninsignaling, increasing the degradation of AXIN by theubiquitin–proteasome pathway [61–63]. Tankyraseinhibitor, XAV939 and IWR-1 regulated AXIN by inhibiting Tankyrase 1 and Tankyrase 2 [64, 65]. Treatment withXAV939 decreased the viability of EOC cell lines andincreased radio-sensitivity in cervical cancer cells [66].Furthermore, the tankyrase-specific inhibitor, JW74 andJW55 affects cell cycle progression and induced apoptosisand differentiation in osteosarcoma and colon carcinomacells, respectively [67, 68]. In addition, mice xenograftsand patient-derived sphere cultures of colorectal cancer(CRC) were incubated with a Tankyrase inhibitor NVPTNKS656 combination with AKT and PI
Targeting the Wnt/β-catenin signaling pathway in cancer Ya Zhang1,2,3,4,5,6 and Xin Wang1,2,3,4,5,6* Abstract The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and dierentia-tion, thus exerting crucial roles in tumorigenesis and t
the Wnt/β-catenin pathway may be involved in the pathophysiology of endometriosis. This is a review of the literature focused on the aberrant activation of the Wnt/β-catenin pathway in patients with endometriosis, and on how targeting the Wnt/targeting pathway may be a potentially effecti
Wnt/β-catenin signaling pathway, the non canonical planar cell polarity (PCP) pathway, and the Wnt/Ca2 pathway [3]. A critical and most studied Wnt pathway is canonical Wnt signaling and is the primary subject of this review. Many reports have suggested that over expressed of
pathway is activated in TNBC patient tissues, which is not attributed to mutations of the genes in this pathway, but to EGFR overexpression12,13. EGFR overexpression can occur through increases in gene copy number9 or transcriptional induction via the Wnt/β-catenin pathway14. The Wnt/ β-catenin p
the Wnt/β-catenin signaling pathway lacks druggable molecular targets, which has hampered the development of therapeutic drugs targeting this pathway. It is un-known whether NAMPT regulates colorectal cancer proliferation through Wnt/β-catenin signaling pathway. If NAMPT could regulate
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
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Leading Edge Review Wnt/b-Catenin Signaling and Disease Hans Clevers1,* and Roel Nusse2 1Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands 2Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA *Correspondence: h.clevers@hubrecht.eu
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