Wnt Signaling and Drug Resistance in Cancer

• Published in: Molecular pharmacology Vol. 97; no. 2; pp. 72 - 89
• Main Authors: Zhong, Zheng, Virshup, David M
• Format: Journal Article
• Language: English
• Published: United States 01.02.2020
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinogenesis - genetics; Clinical Trials as Topic; DNA Damage - drug effects; DNA Repair - genetics; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm - genetics; Humans; Ligands; Molecular Targeted Therapy - methods; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - pathology; Wnt Proteins - antagonists & inhibitors; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - genetics
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.119.117978

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 US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENT: The latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.