Comprehensive analysis of a real-world cohort identifies geranylgeranyl diphosphate synthase 1 as a predictor of chemoresistance in small cell lung cancer

Yi Deng ¹, Chenchen Guo ^2,3,4, Tengfei Zhang ^4,5

¹Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
²Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
⁵University of Chinese Academy of Sciences, Beijing, China.
⁶Department of Pulmonary and Critical Care Medicine, Taikang Xianlin Gulou Hospital, Nanjing, China.
⁷Department of Respiratory, Taikang Xianlin Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
⁸School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
⁹School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.

⁰Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.

International Journal of Cancer +

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July 4, 2025

View abstract on PubMed

Summary

High geranylgeranyl diphosphate synthase 1 (GGPS1) expression predicts chemotherapy resistance in small cell lung cancer (SCLC). GGPS1 may also indicate sensitivity to statin combination therapy in resistant SCLC patients.

Area Of Science

Oncology
Molecular Biology
Cancer Research

Background

Chemotherapy resistance is a significant challenge in small cell lung cancer (SCLC).
Biomarkers to predict intrinsic chemoresistance in SCLC are currently lacking.
Previous research linked high geranylgeranyl diphosphate synthase 1 (GGPS1) expression to poor survival in SCLC and suggested statin efficacy in GGPP-high SCLC.

Purpose Of The Study

To investigate GGPS1 expression patterns in SCLC subtypes.
To clarify the relationship between GGPS1 expression and clinical chemotherapy response.
To validate GGPS1 as a predictor of statin treatment sensitivity in chemoresistant SCLC.

Main Methods

Integrative analysis of 146 real-world SCLC cases.
Subgroup analysis of GGPS1 expression based on SCLC subtypes.
Correlation analysis of GGPS1 expression with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Analysis of paired biopsy samples from chemoresistant SCLC.
Evaluation of etoposide/cisplatin plus statin efficacy in a patient-derived xenograft (PDX) model.

Main Results

Approximately 25% of SCLC cases exhibited high GGPS1 expression.
Higher GGPS1 expression was observed in the ASCL1/NEUROD1/POU2F3 triple-negative subgroup.
High GGPS1 expression significantly correlated with reduced ORR, PFS, and OS.
GGPS1 was upregulated in chemoresistant SCLC.
Combination therapy of etoposide/cisplatin with statins showed improved efficacy in a high-GGPS1 PDX model.

Conclusions

GGPS1 serves as a potential biomarker for predicting chemotherapy resistance in SCLC.
GGPS1 may indicate sensitivity to statin combination therapy in chemoresistant SCLC.
Targeting GGPS1 warrants further investigation for overcoming SCLC chemoresistance.

Keywords:

GGPS1 biomarker chemoresistance small cell lung cancer therapeutic response