Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer

Author:

Lee Jin12ORCID,Mashima Tetsuo1ORCID,Kawata Naomi13ORCID,Yamamoto Noriko4ORCID,Morino Shun12ORCID,Inaba Saori1ORCID,Nakamura Ayane15ORCID,Kumagai Koshi67ORCID,Wakatsuki Takeru3ORCID,Takeuchi Kengo4ORCID,Yamaguchi Kensei3ORCID,Seimiya Hiroyuki125ORCID

Affiliation:

1. 1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.

2. 2Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

3. 3Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

4. 4Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

5. 5Department of Life and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.

6. 6Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

7. 7Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.

Abstract

Abstract Anticancer drug-tolerant persister (DTP) cells at an early phase of chemotherapy reshape refractory tumors. Aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is commonly upregulated by various anticancer drugs in gastric cancer patient-derived cells (PDC) and promotes tumor growth. However, the mechanism underlying the generation of ALDH1A3-positive DTP cells remains elusive. Here, we investigated the mechanism of ALDH1A3 expression and a combination therapy targeting gastric cancer DTP cells. We found that gastric cancer tissues treated with neoadjuvant chemotherapy showed high ALDH1A3 expression. Chromatin immunoprecipitation (ChIP)-PCR and ChIP sequencing analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the bromodomain and extraterminal (BET) inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth. In DTP cells, BRD4, but not BRD2/3, was recruited to the ALDH1A3 promoter and BRD4 knockdown decreased drug-induced ALDH1A3 upregulation. Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell–targeting agents for gastric cancer treatment. Significance: Drug resistance hampers the cure of patients with cancer. To prevent stable drug resistance, DTP cancer cells are rational therapeutic targets that emerge during the early phase of chemotherapy. This study proposes that the epigenetic regulation by BET inhibitors may be a rational therapeutic strategy to eliminate DTP cells.

Funder

MEXT | Japan Society for the Promotion of Science

Nippon Foundation

Takeda Science Foundation

Graduate School of Frontier Sciences, University of Tokyo

Publisher

American Association for Cancer Research (AACR)

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