RRC ID 63255
Author 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.
Title E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.
Journal Cancer Res
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.
Volume 81(4)
Pages 1052-1062
Published 2021-2-15
DOI 10.1158/0008-5472.CAN-20-0782
PII 0008-5472.CAN-20-0782
PMID 33408116
MeSH Animals Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Cell Proliferation / drug effects Cells, Cultured Disease Models, Animal Female Genes, APC HEK293 Cells Humans Mice Mice, Inbred C57BL Mice, Nude Mice, Transgenic Neoplasms / drug therapy Neoplasms / genetics Neoplasms / metabolism Neoplasms / pathology* Peptide Fragments / antagonists & inhibitors Peptide Fragments / metabolism* Protein Binding / drug effects Pyrazines / pharmacology* Pyrazines / therapeutic use Sialoglycoproteins / antagonists & inhibitors Sialoglycoproteins / metabolism* Triazines / pharmacology* Triazines / therapeutic use Wnt Signaling Pathway / drug effects* Wnt Signaling Pathway / genetics Wnt1 Protein / genetics Wnt1 Protein / metabolism beta Catenin / antagonists & inhibitors beta Catenin / metabolism*
IF 9.727
Human and Animal Cells ECC10(RCB0983)