Targeting Bcl-2 as Treatment Strategy – Leukaemia versus Glioblastoma

Glioblastoma is the most common and lethal primary malignancy of the brain. Despite an aggressive treatment strategy that comprises maximal safe surgical resection of the tumour bulk followed by focal fractionated radiotherapy and alkylating chemotherapy with Temozolomide (TMZ), the median patient survival is 14.6 months. To break the intrinsically high apoptosis resistance exhibited by Glioblastoma cells, we investigated the possible potential of the Bcl-2-specific BH3 mimetic Abt-199 (Venetoclax). While we could show that in B cell precursor Acute lymphoblastic leukaemia cells Abt-199 as monotherapy is sufficient to induce cell death, the BH3 mimetic did not affect Glioblastoma stem cell-like cells nor their differentiated progeny on its own and only weakly enhanced the apoptotic effects of TMZ or serum withdrawal.

Investigating the underlying molecular mechanisms in Glioblastoma exposed to Abt-199, we could observe a compensatory upregulation of Mcl-1 upon Bcl-2 inhibition. This known mechanism is insufficient to explain the muted response of Glioblastoma cells to Abt-199 exposure, as additional inhibition of Mcl-1 is insufficient to break apoptosis resistance. We therefore propose additional targets within the Bcl-2 family that need to be modulated to further sensitize Glioblastoma cells for cell death.