Article
ALDH1A1 is a marker for acquired drug resistance in recurrent glioblastoma
ALDH1A1 ist ein Marker für erworbene Chemoresistenz im Glioblastomrezidiv
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Published: | June 26, 2020 |
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Objective: Treatment of glioblastoma (GBM) is limited and fatal relapse occurs almost universally, even in patients that initially benefit from tissue resection, irradiation and chemotherapy with temozolomide. To abolish acquired resistance to temozolomide in recurrent GBM, driving mechanisms need to be identified and targeted.
Methods: We investigated paired samples of primary and recurrent GBM disease and performed in situ, in vitro and in vivo studies on tissue specimen and tissue-derived cell cultures. Treatment approaches were additionally evaluated in an orthotopic xenograft model.
Results: A subset of tumor cells in recurrent GBM exhibits temozolomide-resistance and paired sample analysis revealed elevated levels of phosphorylated AKT in this cell population. In consequence, inhibition of the AKT pathway reversed drug resistance and increased survival in xenograft models. ALDH1A1 is a marker for temozolomide-resistant tumor subclones and combinatorial treatment with temozolomide and an AKT-inhibitor suggested significantly increased survival by decreasing the ALDH1A1-expressing tumor cell population.
Conclusion: ALDH1A1-expressing tumor cells can be targeted in vivo to overcome temozolomide resistance in recurrent GBM.