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Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy
Chenchen Guo1,2, Ruijie Wan1,2, Yayi He3
1State 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.
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.
Insights
Statins target the mevalonate pathway to overcome chemoresistance in small cell lung cancer (SCLC). This approach induces apoptosis and shows promise in preclinical models and patient relapse cases.
Area of Science:
- Oncology
- Metabolic Pathways
- Drug Discovery
Background:
- Small cell lung cancer (SCLC) exhibits significant chemoresistance, limiting effective treatment options.
- Metabolic reprogramming is a key mechanism enabling cancer cells to survive chemotherapy.
Purpose of the Study:
- To identify metabolic vulnerabilities in chemoresistant SCLC.
- To evaluate statins as a therapeutic strategy to overcome SCLC chemoresistance.
Main Methods:
- Established human chemoresistant SCLC xenograft models.
- Investigated the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway.
- Assessed statin efficacy in preclinical models and patient samples.
Main Results:
- Chemoresistant SCLC relies on the MVA-GGPP pathway.
- Statins target the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis, inducing oxidative stress and apoptosis.
- Statin treatment overcame chemoresistance in SCLC models, particularly those with high GGPS1.
- GGPS1 expression correlated with poorer patient survival.
- Combined statin and chemotherapy yielded durable responses in relapsed SCLC patients.
Conclusions:
- The MVA-GGPP pathway is a metabolic vulnerability in SCLC.
- Statins represent a promising therapeutic strategy to overcome SCLC chemoresistance.
- Targeting GGPS1 may improve outcomes for SCLC patients.
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