CRISPR/Cas9-induced knockout reveals the role of ABCB1 in the response to temozolomide, carmustine and lomustine in glioblastoma multiforme

• Published in: Pharmacological research 2022-11, Vol.185, p.106510-106510, Article 106510
• Main Authors: Radtke, Lena, Majchrzak-Celińska, Aleksandra, Awortwe, Charles, Vater, Inga, Nagel, Inga, Sebens, Susanne, Cascorbi, Ingolf, Kaehler, Meike
• Format: Article
• Language: English
• Subjects: ABC transporters; CRISPR; Drug resistance; Glioblastoma; Temozolomide
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2022.106510

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with limited therapeutic options. Besides surgery, chemotherapy using temozolomide, carmustine or lomustine is the main pillar of therapy. However, therapy success is limited and prognosis still is very poor. One restraining factor is drug resistance caused by drug transporters of the ATP-binding cassette family, e.g. ABCB1 and ABCG2, located at the blood-brain barrier and on tumor cells. The active efflux of xenobiotics including drugs, e.g. temozolomide, leads to low intracellular drug concentrations and subsequently insufficient anti-tumor effects. Nevertheless, the role of efflux transporters in GBM is controversially discussed. In the present study, we analyzed the role of ABCB1 and ABCG2 in GBM cells showing that ABCB1, but marginally ABCG2, is relevant. Applying a CRISPR/Cas9-derived ABCB1 knockout, the response to temozolomide was significantly augmented demonstrated by decreased cell number (p