PROTAC EZH2 degrader overcomes podophyllotoxin derivatives-based regimens resistance in refractory SCLC with leptomeningeal metastasis

Leptomeningeal metastases (LM) of small cell lung cancer (SCLC) are highly detrimental occurrences with severe neurological disorders and extremely poor prognosis without effective treatment. The aim of our study was to find a treatment for refractory SCLC with leptomeningeal metastasis which overcomes resistance to podophyllotoxin derivatives-based resistance. To generate a SCLC-LM mouse model, H128 cells were genetically modified with the luciferase gene, mutated by MNNG and inoculated in mice via the carotid artery. SCLC-LM mice were teated with PROTAC EZH2 degrader-1 combined with carboplatin, etoposide, teniposide (VM26) or anlotinib to conduct drug tests in vitro and in vivo. RNA-seq analysis was performed to look for possible molecular targets for leptomeningeal metastases.