Rational targeting of dynamic tumor subclones in relapsing human glioblastoma. Rational targeting of dynamic tumor subclones in relapsing human glioblastoma

Glioblastoma therapy relies on the alkylating drug temozolomide (TMZ) administered to irradiated patients post-neurosurgery, which increases overall survival but cannot prevent fatal disease relapse. Using clinical samples and glioblastoma models, we here identify TMZ-driven enrichment of ALDH1A1+ tumor subclones acquiring AKT-dependent drug resistance en route to relapse. We demonstrate that this recurrent phenotype switch is predictable and can be countered by a sequential rather than simultaneous combinatorial treatment approach. Overall design: Microarray gene expression was conducted on paired (treatment-naive and relapse) patient-derived and experimentally generated IDH wt glioblastoma samples.