Direct Inhibition of β-catenin: A new strategy for colorectal cancer

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among both men and women in the United States and remains an area of significant clinical need. Inactivation of the APC tumor suppressor gene is considered an initiating event and the key oncogenic driver in most CRCs; disruption of APC protein function drives activation of the Wnt/β-catenin signaling pathway. CRCs also harbor a high incidence of other mutations that often arise as a secondary event after Wnt/β-catenin dysregulation (multistep somatic evolution model) such as in KRAS, BRAF, TP53, P13K and/or SMAD4 that cooperate with APC loss to further drive tumor progression [1]. Treatment regimens for advanced unresectable CRC involve combination chemotherapies that are not curative. Current-generation targeted therapies including EGFR, VEGF and VEGFR inhibitors, have achieved mixed results. EGFR inhibitors for example, do not benefit patients with KRAS/BRAF mutations and yield a relatively low response rate. MEK inhibitors are also being explored as a treatment for patients with KRAS/BRAF mutant tumors who are not candidates for EGFR-directed therapies, however, these compounds have yielded limited efficacy to date. A triple-combination regimen of BRAF, MEK, and EGFR inhibitors showed improved progression free survival (PFS) compared to the individual agents, but even this potent cocktail yielded a PFS of only 4.2 months in refractory CRC [2]. Rapid emergence of drug resistance and dose-limiting toxicities have delayed the pace of clinical progress