Therapeutic targeting of β-catenin in cancer.

Abstract

Mutations in β-catenin, together with recurrent genetic alterations affecting the WNT signaling pathway, define one of the most prevalent oncogenic axes, collectively occurring in approximately 10% of human cancers. Thus, β-catenin is a prime target for precision oncology. Over the three decades following the pathway's discovery, substantial progress has been made in elucidating how aberrant WNT/β-catenin signaling can drive cancer initiation, progression and maintenance. Attempts to therapeutically address this pathway have until recently been unsuccessful. Approaches to block the pathway upstream of relevant mutations were ineffective while progress in directly targeting β-catenin, either by blocking its interaction with key complex partners, most notably T cell factor (TCF) proteins, or by inducing β-catenin degradation has long remained an unreachable goal for conventional drug discovery approaches. In this review, we describe opportunities and challenges in the development of therapies that directly aim to target β-catenin. We highlight recent progress based on novel approaches, suggesting that cracking this previously considered "undruggable" central oncogenic driver is becoming a reality. Effective targeting of β-catenin has the potential to address extensive unmet patient needs in hard-to-treat cancer types such as colorectal cancer, hepatocellular carcinoma as well as other cancers driven by WNT/β-catenin pathway alterations.