Statins show promise in solving small cell lung cancer chemoresistance problem

Statins show promise in solving small cell lung cancer (SCLC) chemoresistance problem

SCLC, which accounts for around 15% of lung cancers, is the most aggressive and has the worst prognosis of all lung cancer subtypes, with only a 5% 5-year survival rate. High metastasis and easy drug resistance are the two most prominent features of SCLC. Due to the high metastatic nature of SCLC, most patients have already developed distant metastasis by the time of diagnosis and lost the opportunity of surgical treatment.

Fortunately, chemotherapy is very effective against SCLC, and the vast majority of patients see considerable tumor reduction after treatment. As a result, unlike most solid tumors, SCLC's primary treatment choice is chemotherapy, which makes getting SCLC samples difficult and provides a significant barrier to studying the pathophysiology of SCLC. To make matters worse, SCLC is initially highly susceptible to treatment, but resistance develops fast, resulting in tumor recurrence.

Due to the lack of effective therapeutic drugs, patients with recurrence rarely receive biopsies under medical ethical constraints, and the lack of these drug-resistant samples further leads to a serious lack of understanding of the mechanism of chemotherapy resistance in SCLC. The lack of understanding of the mechanism also hinders the development of new subsequent therapeutic tools, resulting in an endless loop in SCLC research of "difficult to obtain clinical samples—unclear drug resistance mechanism—lack of effective subsequent therapeutic tools—difficult to obtain clinical samples." The paucity of knowledge about the mechanisms of treatment resistance in SCLC has hampered the development of novel therapeutics. The gathering of clinical samples is, without a doubt, the key to breaking this endless loop.

To achieve this, researchers must find clinical drugs that can effectively overcome resistance to chemotherapy in SCLC based on an in-depth study of the mechanisms of resistance, before it is possible to obtain drug-resistant samples and analyze them in detail within the framework of medical ethics. In order to achieve this, international efforts have been made to establish mouse models that can realistically simulate the drug resistance process of clinical SCLC in vitro, such as establishing a mouse transplantation tumor model of patient derived xenograft (PDX) and simulating the process of clinical SCLC chemoresistance through continuous drug administration, hoping to use this as a breakthrough to deeply understand the molecular mechanism of SCLC chemoresistance and to propose potential treatment strategies.

Hongbin Ji's group at the Chinese Academy of Sciences' Center of Excellence in Molecular Cell Science published a study in Nature Cancer titled "Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in SCLC" on April 21, 2022.

The function and mechanism of the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) metabolic pathway in SCLC chemoresistance were revealed in this study, and it was suggested that statins targeting the MVA-GGPP metabolic pathway could be used as a clinical backline therapy to overcome SCLC chemoresistance.

The study used PDX and human SCLC cell line-derived transplant tumor mouse models derived from SCLC patient samples that were treated with chemotherapeutic agents for up to one and a half years to simulate clinical dosing regimens.

By establishing and studying a mouse model of chemoresistance in SCLC, this study revealed the critical role of mevalonate metabolism in chemoresistance in SCLC, and suggested that statins targeting the MVA-GGPP metabolic pathway could be used as a clinical backline therapy to overcome chemoresistance. In addition, the researchers have teamed together to start two phase II clinical trials with the goal of determining the efficacy of statins in combination with chemotherapy in patients with chemoresistant SCLC. Once statin-chemotherapy combinations are shown to be effective, the cycle of "difficult to obtain clinical samples—unclear mechanism of resistance—lack of effective follow-up—difficult to obtain clinical samples" will be broken, laying the groundwork for future comprehensive insights into the molecular mechanisms of chemoresistance in SCLC.

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