Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors

The 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 the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress 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-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.

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Targeting the Wnt/β-catenin signaling pathway in cancer.

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

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Wnt addiction of genetically defined cancers reversed by PORCN inhibition

Wnt/β-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/β-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer. More effective treatments for cancer could be developed by targeting signaling pathway regulators that are expressed solely in cancer cells. Disruption to a major signaling pathway known as Wnt, which is involved in processes including cell proliferation, tissue homeostasis and tissue regeneration, is now recognized as a significant contributor to the development of certain cancers. Jae-Il Park and Youn-Sang Jung at the University of Texas MD Anderson Cancer Center, Houston, USA, reviewed recent research into Wnt signaling in cancer and possible therapies. Scientists have developed Wnt inhibitors for cancer treatment, but these have detrimental side effects including skeletal degeneration and abdominal pain. New studies suggest there are Wnt signaling regulators that are specifically expressed in cancer cells, which may prove to be more effective drug targets than blocking Wnt signaling as a whole.

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex.

Protein lipidation, including cysteine prenylation, N-terminal glycine myristoylation, cysteine palmitoylation, and serine and lysine fatty acylation, occurs in many proteins in eukaryotic cells and regulates numerous biological pathways, such as membrane trafficking, protein secretion, signal transduction, and apoptosis. We provide a comprehensive review of protein lipidation, including descriptions of proteins known to be modified and the functions of the modifications, the enzymes that control them, and the tools and technologies developed to study them. We also highlight key questions about protein lipidation that remain to be answered, the challenges associated with answering such questions, and possible solutions to overcome these challenges.

Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies.

Porcupine is a member of the membrane-bound O-acyltransferase family of proteins. It catalyzes the palmitoylation of Wnt proteins, a process required for their secretion and activity. We recently disclosed a class of small molecules (IWPs) as the first reported Porcn inhibitors. We now describe the structure-activity relationship studies and the identification of subnanomolar inhibitors. We also report herein the effects of IWPs on Wnt-dependent developmental processes, including zebrafish posterior axis formation and kidney tubule formation.

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The Development of Highly Potent Inhibitors for Porcupine

Development of a triazole class of highly potent Porcn inhibitors.

The present disclosure provides compounds that may be useful for inhibiting Wnt pathway comprising compounds of the formula: (Ia) or (Ib) wherein the variables are as defined herein. In some aspects, the compounds may be used to inhibit the Wnt pathway and used to treat cancer, myocardial infarction, osteopetrosis, or used in the maturation of a precursor cell to a mature cell. Also provided herein in are pharmaceutical compositions of the compounds described herein.

Lishu Zhang

Papers

The Development of Highly Potent Inhibitors for Porcupine

Development of a triazole class of highly potent Porcn inhibitors.

Disubstituted and trisubtituted 1,2,3-triazoles as wnt inhibitors