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

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Drug-tolerant persister (DTP) cells that arise early in chemotherapy contribute to the development of refractory tumors. In gastric cancer patient-derived cells (PDCs), the enzyme ALDH1A3 is often upregulated in response to various anticancer drugs and supports tumor progression. However, the process leading to the formation of ALDH1A3-positive DTP cells is not well understood. In this study, we explored the mechanism behind ALDH1A3 expression and investigated a combination therapy aimed at targeting DTP cells in gastric cancer. Our results showed that gastric cancer tissues treated with neoadjuvant chemotherapy exhibited elevated ALDH1A3 levels. Further analysis using chromatin immunoprecipitation (ChIP)-PCR and ChIP sequencing indicated that histone H3 lysine 27 acetylation was enriched at the ALDH1A3 promoter in 5-fluorouracil (5-FU)-tolerant persister PDCs. Through chemical library screening, we identified that bromodomain and extraterminal (BET) inhibitors, such as OTX015/birabresib and I-BET-762/molibresib, effectively suppressed DTP-related ALDH1A3 expression and preferentially inhibited the growth of DTP cells. In DTP cells, BRD4, but not BRD2/3, was found I-BET-762 to bind to the ALDH1A3 promoter, and knocking down BRD4 reduced drug-induced ALDH1A3 upregulation. Additionally, combination therapy with 5-FU and OTX015 significantly inhibited tumor growth in vivo. These findings suggest that BET inhibitors could serve as effective agents for targeting DTP cells in gastric cancer treatment.

Significance: Drug resistance is a major obstacle to curing cancer. Targeting DTP cells, which appear early during chemotherapy, offers a promising strategy to prevent stable drug resistance. This study suggests that using BET inhibitors for epigenetic regulation may be an effective approach to eliminate DTP cells.