E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

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 signaling pathway in HEK293 and adenomatous polyposis coli (APC)-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 sequencing 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 IHC 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 signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/β-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.

• Authors: Kazuhiko Yamada, Yusaku Hori, Satoshi Inoue, Yuji Yamamoto, Kentaro Iso, Hiroshi Kamiyama, Atsumi Yamaguchi, Takayuki Kimura, Mai Uesugi, Junichi Ito, Masahiro Matsuki, Kazutaka Nakamoto, Hitoshi Harada, Naoki Yoneda, Atsushi Takemura, Ikuo Kushida, Naomi Wakayama, Kenji Kubara, Yu Kato, Taro Semba, Akira Yokoi, Masayuki Matsukura, Takenao Odagami, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa, Yasuhiro Funahashi, Yoichi Ozawa
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 4 Pg. 1052-1062 (02 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33408116 (Publication Type: Journal Article)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• CTNNB1 protein, human
• Peptide Fragments
• Pyrazines
• Sialoglycoproteins
• Triazines
• WNT1 protein, human
• Wnt1 Protein
• beta Catenin
• bone sialoprotein (35-62), human
• E-7386

Topics

• Animals
• Antineoplastic Agents (pharmacology, 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, genetics, metabolism, pathology)
• Peptide Fragments (antagonists & inhibitors, metabolism)
• Protein Binding (drug effects)
• Pyrazines (pharmacology, therapeutic use)
• Sialoglycoproteins (antagonists & inhibitors, metabolism)
• Triazines (pharmacology, therapeutic use)
• Wnt Signaling Pathway (drug effects, genetics)
• Wnt1 Protein (genetics, metabolism)
• beta Catenin (antagonists & inhibitors, metabolism)