1. Academic Validation
  2. Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer

Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer

  • Cell Death Dis. 2025 Mar 12;16(1):170. doi: 10.1038/s41419-025-07481-8.
Li-Ping Zhang # 1 Yu-Min Wei # 1 Ming-Jie Luo 2 Shu-Yue Ren 1 Xiang-Wen Zhan 1 Chao Wang 1 Ze-Feng Li 3 Rui-Min Zhu 1 Shuo Yan 1 Yu Cheng 1 Jia-Li Xu 1 Xing-Jiu Yang 1 Ke-Lei Du 2 Jin-Qing Wang 4 Guan-Nan Zhang 5 De-Xiao Du 6 Ran Gao 1 Dong-Bing Zhao 3 Jia-Nan Gong 7
Affiliations

Affiliations

  • 1 National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Department of Gastrointestinal Surgery, The Second Hospital of Shandong University, Jinan, China.
  • 5 Division of Colorectal Surgery, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 6 Department of general surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.
  • 7 National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. gongjianan@cnilas.org.
  • # Contributed equally.
Abstract

Despite the progress of treatment in gastric Cancer (GC), the overall outcomes remain poor in patients with advanced diseases, underscoring the urgency to develop more effective treatment strategies. BH3-mimetic drugs, which inhibit the pro-survival BCL2 family proteins, have demonstrated great therapeutic potential in Cancer therapy. Although previous studies have implicated a role of targeting the cell survival pathway in GC, the contribution of different pro-survival BCL2 family proteins in promoting survival and mediating resistance to current standard therapies in GC remains unclear. A systematic study to elucidate the hierarchy of these proteins using clinically more relevant GC models is essential to identify the most effective therapeutic target(s) and rational combination strategies for improving GC therapy. Here, we provide evidence from both in vitro and in vivo studies using a broad panel of GC cell lines, tumoroids, and xenograft models to demonstrate that BCLXL and MCL1, but not Other pro-survival BCL2 family proteins, are crucial for GC cells survival. While small molecular inhibitors of BCLXL or MCL1 exhibited some single-agent activity, their combination sufficed to cause maximum killing. However, due to the unsolved cardiotoxicity associated with direct MCL1 inhibitors, finding combinations of agents that indirectly target MCL1 and enable the reduction of doses of BCLXL inhibitors while maintaining their anti-neoplastic effects is potentially a feasible approach for the further development of these compounds. Importantly, inhibiting BCLXL synergized significantly with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induced MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppressed MCL1 transcription via the STAT3/SRF axis. Moreover, co-targeting STAT3 and BCLXL also exhibited synergistic killing, extending beyond HER2-amplified GC. Collectively, our results provide mechanistic rationale and pre-clinical evidence for co-targeting BCLXL and MCL1 (both directly and indirectly) in GC. (i) Gastric Cancer cells rely on BCLXL and, to a lesser degree, on MCL1 for survival. The dual inhibition of BCLXL and MCL1 with small molecular inhibitors acts synergistically to kill GC cells, regardless of their TCGA molecular subtypes or the presence of poor prognostic markers. While the effect of S63845 is mediated by both Bax and Bak in most cases, Bax, rather than Bak, acts as the primary mediator of BCLXLi in GC cells. (ii) Inhibiting BCLXL significantly synergizes with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppress MCL1 transcription via the STAT3/SRF axis. The combination of the STAT3 Inhibitor and BCLXL inhibitor also exhibits synergistic killing, extending beyond HER2-amplified GC.

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