Abstract IA14: Targeting the Wnt signaling pathway in cancer

Mutations in the adenomatous polyposis coli (APC) gene, resulting in aberrant Wnt pathway activation, were first identified in hereditary and sporadic colorectal cancers in 1991. Today, 24 years later, there are still no approved Wnt pathway inhibitors on the market. In contrast, oncogenic BRAF mutations were discovered in various solid tumors in 2002. Within 9 years the first RAF inhibitor, vemurafenib, received FDA approval for the treatment of BRAF-mutant metastatic melanoma. Why has it been so difficult to develop Wnt pathway inhibitors?The first and most significant challenge has been to identify protein targets within the Wnt pathway that are amenable to pharmacologic inhibition. Other prominent signaling pathways dysregulated in cancer (for example, the MAPK pathway) consist of a series of activating phosphorylation events carried out by kinases, many of which can be inhibited by small molecules. However, the critical regulatory event in the Wnt pathway is the degradation of the transcriptional co-activator β-catenin by the β-catenin destruction complex, composed of APC, Axin, casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3). Instead of activating the pathway, the kinases CK1 and GSK3 serve an inhibitory role, sequentially phosphorylating the amino terminus of β-catenin, triggering its ubiquitination and degradation. Confident that the Wnt pathway was important for tumorigenesis, albeit difficult to drug, Novartis initiated a high-throughput ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signaling Pathways: Wnt: Oral Presentations - Invited Abstracts Source Type: research