SPDR-01 Paired epithelioid glioblastoma patient-derived xenograft models to evaluate resistant mechanism for molecular target therapy

Epithelioid glioblastoma (E-GBM) arises at younger age, commonly disseminates to cerebrospinal fluid, and results in dismal prognosis. About half of E-GBM harbors BRAF V600E mutation, thus BRAF/MEK inhibitors are expected to be specifically sensitive to E-GBM like other BRAF V600E mutant carcinomas. However, therapeutic effect is limited by the emergence of drug resistance. To overcome this issue, it is crucial to elucidate the treatment resistance mechanisms by clinically representative models. Herein, we establish 2 paired E-GBM patient-derived xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAF V600E, TERT promoter mutations and CDKN2A homozygous deletions. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with standard treatment. The YMG62 patient was refractory to combination therapy. The YMG89 patient was initially responded to dabrafenib, but gradually became resistant and the 2 patients died due to CNS dissemination. Paired PDX models were established from tumors prior and after molecular target therapy. All PDXs were formed as CNS dissemination model, which were recapitulated to the patient characteristics. BRAF/MEK inhibitors strongly suppressed cell viability in primary tumor (YMG89P). However, BRAF/MEK inhibitors became resistant in recurrent tumor (YMG89R). YMG62 paired PDXs were resistant to molecular target therapy. Western blotting indicated retained MAPK signaling pathway and/or increased AKT phosphorylation after BRAF/MEK inhibitors treatment in refractory and recurrent cells, which indicates crucial role of re-activation in the MAPK signaling pathway and/or PI3 kinase pathway for tumor maintenance in BRAF V600E mutant E-GBM. We have done high throughput drug screening to identify compounds to overcome resistant to molecular target therapy. Our established E-GBM paired PDX models recapitulate patient characteristics, which may uncover treatment resistant mechanism and novel therapeutic target in E-GBM.