HZ-A-018, a novel inhibitor of Bruton tyrosine kinase, exerts anti-cancer activity and sensitizes 5-FU in gastric cancer cells

Danjing Liu; Wei Xu; Bin Lin; Cong Ji; Minmin Shen; Shuying Shen; Junjie Ma; Xinglu Zhou; Youyou Yan; Bo Zhang; Nengming Lin

doi:10.3389/fphar.2023.1142127

HZ-A-018, a novel inhibitor of Bruton tyrosine kinase, exerts anti-cancer activity and sensitizes 5-FU in gastric cancer cells

Front Pharmacol. 2023 Mar 22:14:1142127. doi: 10.3389/fphar.2023.1142127. eCollection 2023.

Authors

Danjing Liu^{1

2}, Wei Xu^{1

2}, Bin Lin^{1

3}, Cong Ji^{1

2}, Minmin Shen^{1

4}, Shuying Shen¹, Junjie Ma^{1

2}, Xinglu Zhou⁵, Youyou Yan², Bo Zhang^{1

2

6}, Nengming Lin^{1

2

6

7}

Affiliations

¹ College of Pharmaceutical Sciences, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
² Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China.
³ Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Changxing People's Hospital, Huzhou, Zhejiang, China.
⁴ Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China.
⁵ Hangzhou Hezheng Pharmaceutical Co., Ltd., Huzhou, Zhejiang, China.
⁶ Cancer Center, Zhejiang University, Huzhou, Zhejiang, China.
⁷ Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Huzhou, Zhejiang, China.

Abstract

Gastric cancer is the third leading cause of cancer related death worldwide. Due to the complexity and heterogeneity of gastric cancer, the development of targeted drugs is somehow limited, but is urgently needed. Since the expression of Bruton tyrosine kinase (BTK) was significantly associated with the prognosis of gastric cancer patients, we aimed to determine the anti-cancer activity of HZ-A-018, which was a novel derivative of ACP-196, in gastric cancer cells. As a result, HZ-A-018 presented a stronger anti-proliferation activity than ACP-196 via the substantial suppression of AKT/S6 pathway. In addition, HZ-A-018, but not ACP-196, exerted the synergistic effects in combined treatment with 5-FU both in vitro and in vivo, without exacerbating the adverse effects of 5-FU. Mechanismly, the combination of HZ-A-018 and 5-FU remarkably reduced the expression of RRM2, which played an essential role in proliferation and drug sensitivity in gastric cancer cells. In summary, our work demonstrated the stronger anti-cancer activity of HZ-A-018 than ACP-196 in gastric cancer cells, and revealed synergistic effects of HZ-A-018 and 5-FU combination probably through the inhibition of RRM2 via AKT/S6 pathway, thereby providing a promising therapeutic strategy in gastric cancer.

Keywords: 5-FU; Akt; Bruton tyrosine kinase; RRM2; gastric cancer.

Grants and funding

This work was supported by National Natural Science Foundation (82073297), Natural Science Foundation of Zhejiang Province (LY20H310005), Zhejiang Provincial Program for the Cultivation of High-level Leading Health Talents (2020-18), Clinical Pharmacy of Hangzhou Medical Key Discipline (2021-21-16), Zhejiang Chinese Medical University Graduate Science Foundation Program (2021YKJ27).