Tmod-22. differential drug sensitivity analysis in paired patient-derived cell lines of glioblastoma

Abstract Glioblastoma (GBM) remains the most aggressive adult brain tumour with dismal prognosis. Even when treated by the most optimal standard-of-care modalities, disease progression remains consistently inevitable. Understanding how tumours evolve from a newly diagnosed to a recurrent setting is therefore critical, but research models to functionally test how therapeutic interventions evolve accordingly remain scarce. Here, we describe our efforts to develop paired models including newly diagnosed and recurrent GBM cell lines derived from the same patients. Overall, we collected 50 tumour samples originating from 24 patients at different time points in their treatment scheme. This resulted in the generation of 27 models overall, from which 18 originated from 9 patients at different timepoints. The latter were subsequently investigated extensively. First, using genomic profiling, we consistently observed an increase in mutational burden and chromosomal aberrations in the recurrent samples, while transcriptomic profiling showed that tumour subtypes evolved in a very patient-specific way. A large fraction of the recurrent models showed resistance to temozolomide (TMZ), which coincided with a downregulation of DNA repair (MMR) pathways or mutations. Half of the tested models also acquired resistance to radiation therapy. Next to standard-of-care therapy, we investigated several small molecule inhibitors that are currently in clinical evaluation, which also showed differential sensitivity. Overall, the developed paired cell lines recapitulate the most important features related to tumour recurrence, and offer the opportunity for more elaborate dependency screening efforts.