2022 World Conference on Lung Cancer (ePosters)-EP14.02-005. Therapeutic Targeting Mevalonate-Geranylgeranyl Diphosphate Pathway with Statins Overcomes Chemotherapy-resistance in SCLC

EP14.02-005. Therapeutic Targeting Mevalonate-Geranylgeranyl Diphosphate Pathway with Statins Overcomes Chemotherapy-resistance in SCLC

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Chemotherapy resistance is a major challenge in the treatment of small cell lung cancer (SCLC), and there is a need for new therapeutic strategies. This study aimed to understand the metabolic changes that occur during SCLC chemotherapy resistance and determine if targeting these metabolic alterations can be an effective therapeutic approach. The researchers established SCLC patient-derived xenograft (PDX) models and chemoresistant xenograft models through long-term chemotherapy. They found that chemoresistant SCLC tumors undergo metabolic reprogramming towards the mevalonate-geranylgeranyl diphosphate (MVA-GGPP) pathway. Through drug screenings and mechanistic studies, they discovered that statins, a class of FDA-approved drugs, can target this metabolic pathway and overcome chemoresistance in SCLC. They also found that a higher expression of GGPS1, a key enzyme in the MVA-GGPP pathway, is associated with poor prognosis in SCLC patients. In addition, the study showed that combined treatment with statins and chemotherapy led to significant and long-lasting responses in three SCLC patients who had relapsed from first-line chemotherapy. The researchers also identified the mechanism by which statins induce apoptosis and overcome chemoresistance in SCLC cells through the GGPS1-RAB7A-autophagy axis. These findings suggest that targeting the MVA-GGPP pathway with statins can be a novel and practical strategy for treating chemotherapy-resistant SCLC with high GGPS1 expression. The researchers have initiated two phase II clinical trials to further evaluate the efficacy of statins in SCLC patients who have relapsed from first-line treatment. The results from these trials will provide more clinical evidence for the use of statins in overcoming chemoresistance and explore the potential of GGPS1 as a biomarker in SCLC.

Asset Subtitle

Chenchen Guo

Meta Tag

Speaker Chenchen Guo

Topic Small Cell Lung Cancer and Neuro-endocrine Tumours - Preclinical/Translational

Keywords

Chemotherapy resistance

small cell lung cancer

metabolic changes

SCLC chemotherapy resistance

statins

GGPS1 expression

combined treatment

chemoresistance

apoptosis

clinical evidence