Research reveals the mechanism of chemotherapy resistance in small cell lung cancer and strategies to overcome it

On April 21, Nature Cancer published online the title of Therapeutic targeting of the mevalonate–geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell by Ji Hongbin's research group of the Center for Excellence in Molecular and Cell Science (Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences Research results of lung cancer
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This study revealed the function and mechanism of mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) metabolic pathway in chemoresistance in small cell lung cancer, and proposed a new strategy for targeted therapy
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Small cell lung cancer accounts for about 15% of lung cancers and is the subtype with the highest degree of malignancy and the worst prognosis among all lung cancer subtypes
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High metastasis and susceptibility to drug resistance are two notable features of SCLC
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Due to the high metastatic nature of small cell lung cancer, most patients have developed distant metastasis at the time of diagnosis and lost the opportunity for surgical treatment
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Fortunately, SCLC is very sensitive to chemotherapy, and the vast majority of patients experience significant tumor regression after chemotherapy
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Therefore, unlike the vast majority of solid tumors, the preferred treatment for small cell lung cancer is not surgery but chemotherapy, which directly makes it very difficult to obtain small cell lung cancer samples and hinders the study of the pathogenesis of small cell lung cancer
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In addition, although SCLC is initially highly sensitive to chemotherapy, drug resistance emerges quickly leading to tumor recurrence
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Due to the lack of follow-up effective treatment drugs, relapsed patients are less able to undergo biopsy under the restrictions of medical ethics, and the lack of these drug-resistant samples further leads to insufficient understanding of the current chemoresistance mechanism of small cell lung cancer; This creates obstacles to the development of follow-up new treatment methods, and eventually leads to the research field of small cell lung cancer falling into an endless cycle of "difficulty in obtaining clinical samples - unclear drug resistance mechanism - lack of effective follow-up treatment methods - difficult to obtain clinical samples"
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The key to opening the infinite loop lies in the acquisition of clinical samples
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In order to achieve this goal, researchers must find clinical drugs that can effectively overcome the drug resistance of small cell lung cancer on the basis of in-depth study of the chemoresistance mechanism of small cell lung cancer, and it is possible to obtain drug resistance samples under the framework of medical ethics.
Perform detailed analysis
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In order to achieve this, international efforts have been made to establish a mouse model in vitro that can truly simulate the drug resistance process of clinical small cell lung cancer, such as establishing a mouse xenograft model (PDX) of patient-derived tumors and simulating the drug through continuous administration.
The clinical process of chemotherapy resistance in small cell lung cancer, hoping to use this as a breakthrough to deeply understand the molecular mechanism of small cell lung cancer chemotherapy resistance, and to propose potential treatment strategies
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Although gratifying progress has been made in the field of chemoresistance research in small cell lung cancer in recent years, there are no reports of clinical drugs that can be used to overcome chemoresistance in small cell lung cancer
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　　In this study, by establishing xenografts (PDX) derived from small cell lung cancer patient samples and xenograft mouse models derived from human small cell lung cancer cell lines, the mouse models were treated with chemotherapy for up to one and a half years by simulating the clinical dosing regimen.
After drug treatment, multiple mouse models of small cell lung cancer chemotherapy resistance were finally established
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On this basis, the researchers specifically used a drug library containing 1971 FDA-approved drugs to screen for potential drugs that can specifically inhibit the survival of chemotherapy-resistant cells
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Studies have found that statins, which inhibit the mevalonate metabolic pathway, can significantly inhibit the survival of chemotherapy-resistant cells
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Using another 256 US FDA-certified metabolic drug library for screening and verification, it was also found that a variety of statins can specifically inhibit the survival of chemotherapy-resistant cells
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The researchers speculated that chemotherapy-resistant SCLC may undergo metabolic reprogramming and rely on the mevalonate metabolic pathway to maintain cell survival
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Further mechanism studies have found that statins mainly block the geranylgeranylation modification process of the small G protein RAB7A by inhibiting the production of geranylgeranyl diphosphate in the metabolic pathway of mevalonate.
These cells are unable to function properly on the upper membrane, which in turn inhibits the fusion of autophagosomes and lysosomes, triggers autophagic flow barriers, and promotes excessive accumulation of ROS in drug-resistant cells, leading to apoptosis
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　　Using a series of PDX models of acquired and primary resistance, the researchers further searched for tumor markers that responded better to statin therapy
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The study found that drug-resistant tumors with high expression of geranylgeranyl diphosphate synthase GGPS1 are very sensitive to statins, and chemotherapy combined with statins can significantly overcome the chemoresistance of small cell lung cancer
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Analysis of clinical samples showed that patients with small cell lung cancer with high GGPS1 expression tended to have a worse prognosis
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The study also found that three patients with chemotherapy-resistant small cell lung cancer received varying degrees of remission after receiving chemotherapy combined with simvastatin treatment
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　　In summary, this study revealed the important role of mevalonate metabolism in the chemoresistance of small cell lung cancer by establishing and studying a mouse model of small cell lung cancer chemotherapy resistance, and proposed that statins can be used to target MVA-GGPP metabolic pathway as a strategy to overcome chemoresistance in small cell lung cancer for later-line clinical treatment
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In addition, the investigators collaborated to initiate two Phase 2 clinical studies to further evaluate the efficacy of statins combined with chemotherapy in patients with chemotherapy-resistant small cell lung cancer
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Once statins combined with chemotherapy are proven to be effective, it will open the endless cycle of "difficulty in obtaining clinical samples - unclear drug resistance mechanism - lack of effective follow-up treatments - difficult to obtain clinical samples", which will provide a comprehensive and in-depth understanding of chemotherapy resistance in small cell lung cancer.
The molecular mechanism of small cell lung cancer has laid the foundation stone, which will help the precise treatment of patients with small cell lung cancer chemotherapy-resistant and improve the clinical treatment of patients with small cell lung cancer
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　　The research work is supported by the Animal Experiment Technology Platform, Chemical Biology Platform, Cell Biology Platform and Molecular Biology Platform of the Public Technology Service Center of the Center of Excellence for Molecular Cells.
etc.
funding
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Model diagram of statins overcoming chemoresistance in small cell lung cancer by targeting the MVA-GGPP metabolic pathway Source: Center for Excellence in Molecular and Cell Science, Chinese Academy of Sciences