| 著者 |
Yamada K, Hori Y, Inoue S, Yamamoto Y, Iso K, Kamiyama H, Yamaguchi A, Kimura T, Uesugi M, Ito J, Matsuki M, Nakamoto K, Harada H, Yoneda N, Takemura A, Kushida I, Wakayama N, Kubara K, Kato Y, Semba T, Yokoi A, Matsukura M, Odagami T, Iwata M, Tsuruoka A, Uenaka T, Matsui J, Matsushima T, Nomoto K, Kouji H, Owa T, Funahashi Y, Ozawa Y.
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| Abstract |
The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between β-catenin and CREB binding protein, which is part of the Wnt/β-catenin signaling pathway, disrupts the Wnt/β-catenin signal pathway in HEK-293 and APC (adenomatous polyposis coli)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin/+ mice in which mutation of Apc activates the Wnt/β-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA-Seq data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and immunohistochemical analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/β-catenin signal pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody.
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