1. Academic Validation
  2. Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy

Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy

  • Theranostics. 2019 Jul 9;9(17):4878-4892. doi: 10.7150/thno.36254.
Zhe Zhang 1 Wei Gao 1 Li Zhou 1 Yan Chen 1 Siyuan Qin 1 Lu Zhang 1 Jiayang Liu 1 Yujia He 2 Yunlong Lei 3 Hai-Ning Chen 4 Junhong Han 1 Zong-Guang Zhou 4 Edouard C Nice 5 Changlong Li 2 Canhua Huang 1 Xiawei Wei 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
  • 2 West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P. R. China.
  • 3 Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, P. R. China.
  • 4 Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
  • 6 Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Abstract

Rationale: The sustained and severe endoplasmic reticulum (ER) stress in Cancer cells may contribute to apoptotic cell death, thus representing a potential target for Cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung Cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods: ALK-positive NSCLC cells and various human ALK-negative Cancer cells, especially human colorectal Cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with Autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results: Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of Apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a Deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with Autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion: The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and Autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.

Keywords

ALK independence; Brigatinib; Colorectal cancer; ER stress; ER-phagy.

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