In a study published in Nature Cancer, Dr. JI Hongbin's team from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, reported that chemotherapy-resistant small cell lung cancer (SCLC) has undergone metabolic reprogramming and become addicted to the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, and statin might serve as a potential effective drug for overcoming chemotherapy-resistance in SCLC in clinic.

SCLC, accounting for about 15% of all lung cancer, is the most malignant and deadliest subtype, and holds a 5-year survival rate at only 5%. Chemotherapy-resistance is the central problem for SCLC clinical management and effective therapeutic strategy is urgently needed to improve the prognosis of SCLC patients relapsed from chemotherapy. Up to now, little is known about the role of metabolic alteration in SCLC chemotherapy-resistance. Moreover, whether chemotherapy-resistant SCLC is addicted to metabolic rewiring that can be therapeutically exploited remains to be clarified.

The paucity of tumor specimens from chemotherapy-resistant SCLC patients has greatly hindered current mechanistic understanding of chemotherapy-resistance in clinic. To overcome this, researchers have recapitulated the acquisition of SCLC chemotherapy-resistance in patient-derived xenograft (PDX) mouse models as well as human cell line xenograft mouse models, through intermittent chemotherapy mimicking clinical-relevant therapeutic strategy for up to one and a half years of treatments.

Through two different FDA-approved drug library screenings and integrative studies of these chemotherapy-resistant mouse models, researchers revealed that chemotherapy-resistant SCLC have undergone systematic metabolic reprogramming towards the MVA-GGPP pathway. The MVA pathway is known important for cholesterol synthesis. However, in chemotherapy-resistant SCLC, the metabolic reprogramming is preferentially switched to the GGPP production and protein geranylgeranylation, which in turn activates RAB7A and protects cancer cells from cytotoxic reactive oxygen species (ROS) stress by activation of the autophagic flux and clearance and recycling of damaged proteins and DNAs. These findings provided novel insight into SCLC chemotherapy-resistance mechanism.

Besides, researchers identified the MVA pathway as the vulnerability of chemotherapy-resistant SCLC, especially for those with elevated levels of geranylgeranyl diphosphate synthase 1 (GGPS1), which is closely correlated with GGPP levels. They observed a significant correlation of high GGPS1 level with poor prognosis in Chinese SCLC patients as well as Caucasian population. The finding that targeting of the MVA-GGPP pathway with statins could effectively inhibit chemotherapy-resistant tumor growth in GGPS1^high PDX models makes GGPS1 as a potentially important biomarker for guiding statin treatment in chemotherapy-resistant patients with SCLC.

More importantly, researchers found that statin plus chemotherapy is effective in three SCLC patients who are relapsed from first-line chemotherapy. All the three patients showed regression of primary tumors and/or metastatic tumors at various extents and improved clinical symptoms. Researchers have launched two phase II clinical trials (NCT04698941 and NCT04985201) to evaluate the efficacy of statin adjuvant therapy in SCLC patients who are relapsed from first-line treatments.

Chemotherapy remains as the first-line treatment for SCLC since 1970s and no effective chemotherapy-resistance overcoming therapeutic has been developed thereafter. This is largely attributed to the extreme difficulty in obtaining biopsy specimens from chemotherapy-relapsed patients due to the ethical issues for comprehensive mechanistic analyses. If statin treatment is proven as a new molecular targeted therapy for relapsed patients with high GGPS1 expression, this work will certainly open the door for ethical-approved biopsies in SCLC in clinic. This will hopefully pioneer the potential molecular targeted therapy and precision medicine in SCLC clinical practice, and eventually benefit SCLC patients.