WNT974 / Novartis - LARVOL DELTA

Phase I study of WNT974 in combination with spartalizumab in patients with cutaneous melanoma (ESMO 2024) - P1 | "WNT974 + spartalizumab was well-tolerated and demonstrated preliminary antitumor activity in pts with advanced melanoma who progressed on prior anti-PD-1-based therapy."

Clinical • Combination therapy • IO biomarker • P1 data • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Inhibition of the Wnt/β-Catenin pathway via an LGK974-cyclodextrin inclusion complex alleviates cardiac injury. (PubMed, Biomed Pharmacother) - "These findings indicate that CD:LGK974 attenuates cardiac injury and modulates immune response in T. cruzi-infected mice. Together, these results highlight its potential as a therapeutic strategy for reducing pathological cardiac remodeling associated with T. cruzi infection."

Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Immunology • Infectious Disease • Inflammation • Myocardial Infarction • CD4 • CD8 • IL10

WNT pathway mutations influence response to EGFR and BRAF inhibition in MSS BRAF-V600E metastatic colorectal cancer PDOs (EACR 2026) - "PDOs with either RNF43 mutation or RSPO3-fusion displayed selective sensitivity to WNT ligand inhibition (LGK-974; mean drug sensitivity score (DSS) 25.52 vs 2.02 in APC-mutant PDOs, p-adj = 0.008), confirming high dependence on WNT ligands in these models. In a panel of four selected PDO models harboring different WNT signaling member alterations, the drug combination targeting EGFR (afatinib) and BRAF (encorafenib) demonstrated highest synergy (Bliss Synergy Score > 20) and sensitivity (Combination Sensitivity Score > 50) in the RNF43-mutant PDO model... The study suggests that RNF43 mutations are associated with increased sensitivity to EGFR and BRAF dual inhibition in BRAFV600E-mutated metastatic colorectal cancer. Drug combination experiments revealed superior response and synergy along with apoptotic signaling in an"

Metastases • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • APC • EGFR • RNF43 • RSPO3

The temporal architecture of the seminiferous epithelial cycle revealed by spatial transcriptomics. (PubMed, Cell) - "This cyclicity persists in germ-cell-depleted testes (busulfan and W/Wv), although with gene-specific dephasing and reduced amplitude, supporting an intrinsic Sertoli cyclic program. Notably, Wnt inhibition with LGK974 partially recapitulates germ-cell-depletion dephasing and amplitude changes. These findings support an integrative model where an intrinsic Sertoli program maintains baseline periodicity, while germ-cell signals refine the cycle to coordinate spermatogenesis."

Journal

Epithelial cell adhesion molecule induces canonical Wnt pathway to promote stemness in colorectal cancer (AACR 2024) - "Our EpCAM-neutralizing antibody (EpAb2-6) and a porcupine inhibitor (LGK974) each partially attenuated cancer stemness, while their combination abolished stemness-related endpoints, induced apoptosis in vitro and markedly diminished tumor progression in animal models of human CRC...Our findings reveal an opportunity to combat drug resistance in tumor stem cells. Thus, the mechanistic insights gained from our study may be useful to improve existing treatments or to develop novel anticancer therapeutics."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FZD6 • KRAS

Electroacupuncture Ameliorates Colonic Mucosal Barrier Damage and Inflammation in T2DM Rats by Regulating Enteric Glial Cells Activation in Colon Through the Wnt/β-Catenin/NF-κB Pathway. (PubMed, Neurogastroenterol Motil) - "Electroacupuncture (EA) ameliorates the integrity and functionality of the colonic mucosal barrier while mitigating inflammatory responses in T2DM by regulating excessive EGCs activation through activating the Wnt/β-catenin pathway, suppressing NF-κB signal transmission."

Journal • Preclinical • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • CCND1 • IL6 • MYC • NFKBIA • TNFA • WNT3A

Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation. (PubMed, Exp Ther Med) - "Although antifibrotic agents such as pirfenidone and nintedanib can slow disease progression, these agents fail to reverse established structural damage, underscoring the urgent need for novel therapeutic strategies...The present study aimed to elucidate the role of WNT signaling in IPF pathogenesis, and to evaluate the antifibrotic and anti-inflammatory effects of the WNT inhibitors ETC-159 and LGK-974 in vitro...In conclusion, aberrant activation of WNT signaling may contribute to fibrogenesis and inflammation in IPF. Pharmacological inhibition of this pathway, particularly with LGK-974, exerts potent antifibrotic and anti-inflammatory effects, highlighting WNT signaling as a viable therapeutic target for IPF."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • IL1B • IL6 • TGFB1 • WNT7A

Targeting circGDI2 disrupt HNRNPC-mediated mPORCN stabilization and enhance LGK-974 anti-tumor therapy in hepatocellular carcinoma. (PubMed, Mol Cancer) - No abstract available

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • HNRNPC

FOXK1 induced upregulation of KIF20A promotes hepatocellular carcinoma progression via Wnt/β-Catenin/EMT signaling. (PubMed, Cell Mol Life Sci) - "Wnt pathway activator SKL2001 and inhibitor LGK974 confirmed KIF20A's role in tumor progression...ChIP-seq and promoter assays verified FOXK1's direct binding to the KIF20A promoter, activating its transcription. In conclusion, KIF20A serves as a diagnostic and prognostic biomarker promoting HCC progression via Wnt/β-catenin signaling, regulated by FOXK1, offering new therapeutic targets."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CDH2 • KIF11 • KIF13A • KIF20A • KIF5B • SNAI2 • TWIST1

Regulation of the AKT/Wnt/β-catenin Pathway and Induction of Cuproptosis by Curcumin in Glioblastoma. (PubMed, J Vis Exp) - "A172 and U251 cells were treated with CUM, AKT inhibitor MK-2206, Wnt inhibitor LGK974, and Elsm-Cu (Elesclomol + CuCl2). In nude mice, CUM significantly reduced tumor growth, promoted cuproptosis, and inhibited AKT/Wnt/β-catenin axis activation. Our results indicate that CUM suppresses AKT/Wnt/β-catenin signaling, promotes cuproptosis, and interferes with GBM progression."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Single-cell and immune-context integration identifies basement-membrane/metastasis signatures that sharpen bladder-cancer diagnosis and prognosis. (PubMed, Discov Oncol) - "The MBRG-based model effectively predicts BLCA prognosis, integrates mechanisms of basement membrane remodeling, EMT, and immune suppression, and identifies DDR2 and SERPINF1 in CAFs as potential targets for personalized therapy."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAFs • CD8 • DDR2 • HSPG2 • SLIT2 • TMB

Targeting the tumor cell-intrinsic ITGB2 axis inhibits melanoma progression. (PubMed, Mol Cancer) - "This work overturns the longstanding paradigm that ITGB2 is restricted to leukocytes by discovering a tumor cell-intrinsic ITGB2:ICAM-1:Wnt protumorigenic axis as a bona fide cancer therapeutic target in melanoma."

Journal • Melanoma • Solid Tumor • ICAM1 • IL2 • ITGB2

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (SNO 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • GZMB • WNT7B

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (SNO 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • GZMB • WNT7B

NF2/Merlin loss induces upregulation of an alternative Wnt5a/b signaling pathway sensitive to YAP inhibition (SNO 2025) - "In primary NF2-mutant meningioma lines, targeting this pathway via blocking Wnt secretion with the inhibitor LGK974 or YAP signaling with verteporfin, which is FDA approved, results in decreased cell viability and proliferation in vitro. These results indicate activation of the Wnt5a/b-YAP/TAZ alternative signaling pathway in NF2-mutant meningeal and Schwann cells, and a potential therapeutic effect of blocking this pathway in NF2-mutant meningiomas with a previously-FDA approved inhibitor. Additional research is needed on the receptors and molecular mediators playing a role in this pathway and how these drugs may have therapeutic benefits in vivo"

Alzheimer's Disease • Ataxia • Brain Cancer • CNS Disorders • Cognitive Disorders • Meningioma • Movement Disorders • Otorhinolaryngology • Solid Tumor • Ventriculomegaly • CTNNB1 • NF2

Wnt5a Regulates Focal Adhesion Formation to Promote Migration in Ewing Sarcoma. (PubMed, Cancers (Basel)) - "We have previously reported that WNT974, a selective Porcn inhibitor, delays the onset of metastases in three different xenograft models of Ewing sarcoma with no effect on primary tumor growth, suggesting a specific role of the drug in metastasis...Crispr-Cas9 editing of Wnt5a results in an inability of the cells to migrate with a global lack of filamentous actin in the cell cytoskeleton. These findings suggest that a Wnt5a-dependent signaling pathway drives the cytoskeletal changes and cell adhesion molecule changes necessary for early steps of migration in the metastatic cascade."

Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • VCL

Wnt5a-mediated Adipo-Cardiac Interorgan Communication in HFpEF. (PubMed, bioRxiv) - "Wnt5a exposure increased cardiomyocyte hypertrophy in vitro , and LGK974 (PORCN inhibitor) treatment in vivo decreased circulating Wnt5a levels and improved cardiac remodeling in HFpEF. Our study identifies a novel crosstalk mechanism between cardiomyocytes and adipocytes in obesity-associated HFpEF driven by natriuretic peptide-mediated inhibition of release of Wnt5a from adipocytes."

Journal • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Obesity • NPR3 • WNT5A

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (WFNOS 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • CD8 • GZMB • WNT7B

Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma (WFNOS 2025) - "Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion.Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Clinical • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • GZMB • WNT7B

NF2/Merlin loss induces upregulation of an alternative Wnt5a/b signaling pathway sensitive to YAP inhibition (WFNOS 2025) - "In primary NF2-mutant meningioma lines, targeting this pathway via blocking Wnt secretion with the inhibitor LGK974 or YAP signaling with verteporfin, which is FDA approved, results in decreased cell viability and proliferation in vitro. These results indicate activation of the Wnt5a/b-YAP/TAZ alternative signaling pathway in NF2-mutant meningeal and Schwann cells, and a potential therapeutic effect of blocking this pathway in NF2-mutant meningiomas with a previously-FDA approved inhibitor. Additional research is needed on the receptors and molecular mediators playing a role in this pathway and how these drugs may have therapeutic benefits in vivo"

Alzheimer's Disease • Ataxia • Brain Cancer • CNS Disorders • CNS Tumor • Cognitive Disorders • Meningioma • Movement Disorders • Oncology • Otorhinolaryngology • Solid Tumor • Ventriculomegaly • CTNNB1 • NF2

B4GALT1 and Wntless collaborate to block LRP5/6 translocation from Golgi to cell surface. (PubMed, J Cell Biol) - "Accordingly, LGK974-targeted uncoupling of the Wnt/Wntless complex is able to enhance LRP5/6 Golgi retention, thereby attenuating LRP5/6 cell surface translocation. Taken together, the surface presentation of LRP5/6 is regulated by the Golgi-resident B4GALT1 as well as the Wnt secretion activity."

Journal • Dyslipidemia

BUB1B Promotes Ovarian Cancer Cell Proliferation and Metastasis by Activating the Wnt/β-Catenin Pathway. (PubMed, Cancer Med) - "BUB1B is an oncogene whose expression level is negatively correlated with the prognosis of OC patients. Mechanically, BUB1B promotes the progression of OC via the Wnt/β-catenin pathway. Our study offers a potential therapeutic target for OC treatment."

Journal • Oncology • Ovarian Cancer • Solid Tumor • BUB1 • BUB1B

Inhibition of Wnt Signaling Attenuates Inflammatory Arthritis Severity (ACR Convergence 2025) - "Mice were given daily intraperitoneal injections of the Wnt signaling inhibitor LGK974 or a vehicle control on days 0-4... Collectively, our findings demonstrate the utility of Wnt pathway inhibition in reducing inflammatory arthritis severity. This work identifies a novel fibroblast-targeted therapeutic avenue for RA with a compelling potential value for patients whose disease is recalcitrant to conventional treatment modalities."

Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CXCL5 • SOCS1 • SOCS3

Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma. (PubMed, Proc Natl Acad Sci U S A) - "Treatment combining a porcupine inhibitor WNT974 with αPD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors...Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b/β-catenin inhibition with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD8 • WNT7B

EXPRESS: Exacerbation of paclitaxel-induced neuropathic pain behaviors in breast tumor-bearing mice. (PubMed, Mol Pain) - "Paclitaxel-induced neuropathic pain model in breast tumor-bearing female MMTV-PyMT mice may be a useful animal model for investigating the analgesic effects and underlying mechanisms for CINP in breast cancer patients as well as the interplay between CINP development and cancer progression."

Journal • Preclinical • Breast Cancer • Neuralgia • Oncology • Pain • Solid Tumor