Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

• Main Authors: Hee Eun Kang, Yoojeong Seo, Jun Seop Yun, Sang Hyun Song, Dawool Han, Eunae Sandra Cho, Sue Bean Cho, Yoon Jeon, Ho Lee, Hyun Sil Kim, Joyeon Kang, Jong In Yook, Nam Hee Kim, Tae Il Kim
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Cancers
• Subjects: colorectal cancer; Wnt; Hippo; niclosamide; metformin
• Online Access: https://www.mdpi.com/2072-6694/13/14/3437

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.