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  3. Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

  • Nat Cancer. 2022 May;3(5):614-628. doi: 10.1038/s43018-022-00358-1.
Chenchen Guo  # 1 2,  Ruijie Wan  # 1 2,  Yayi He  # 3,  Shu-Hai Lin 4,  Jiayu Cao 1 2,  Ying Qiu 1 2,  Tengfei Zhang 1 2,  Qiqi Zhao 1 2 5,  Yujia Niu 4,  Yujuan Jin 1,  Hsin-Yi Huang 1,  Xue Wang 1,  Li Tan 6,  Roman K Thomas 7 8 9,  Hua Zhang 10,  Luonan Chen 1 2 5,  Kwok-Kin Wong 10,  Liang Hu 11,  Hongbin Ji 12 13 14 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, China.
  • 5 School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
  • 6 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 7 Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany.
  • 8 Department of Pathology, Medical Faculty, University Hospital Cologne, Cologne, Germany.
  • 9 DKFZ, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
  • 10 Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • 11 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. liang.hu@sibcb.ac.cn.
  • 12 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. hbji@sibcb.ac.cn.
  • 13 University of Chinese Academy of Sciences, Beijing, China. hbji@sibcb.ac.cn.
  • 14 School of Life Science and Technology, Shanghai Tech University, Shanghai, China. hbji@sibcb.ac.cn.
  • 15 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. hbji@sibcb.ac.cn.
  • # Contributed equally.
PMID: 35449308 DOI: 10.1038/s43018-022-00358-1
Abstract

Small cell lung Cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and Apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.

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