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