TY - JOUR T1 - Wnt signaling and drug resistance in cancer JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.117978 SP - mol.119.117978 AU - Zheng Zhong AU - David M. Virshup Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/12/01/mol.119.117978.abstract N2 - Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right". Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing FDA- approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for cancer patients.SIGNIFICANCE STATEMENT We review the latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer. Recent studies extend our understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer. ER -