Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage
Menée in vitro et à l'aide de modèles murins de glioblastome avec mutation du promoteur TERT, cette étude met en évidence un mécanisme par lequel l'inhibition de TERT, via la réduction de l'expression de la protéine GABPB1L, sensibilise les cellules cancéreuses aux dommages causés à l'ADN
Glioblastoma is a highly lethal form of brain cancer with no current treatment options that substantially improve patient outcomes. A key therapeutic challenge is the identification of methods that reduce tumor burden while leaving normal cells unaffected. We show that TERT-promoter mutations, common in glioblastoma, lead to TERT reactivation through increased binding of GABPB1L-isoform–containing transcription factor complexes. In turn, we find that cancer-cell–specific inhibition of TERT through GABPB1L reduction results in near-term anti-growth effects and an impaired DNA damage response that profoundly increase the sensitivity of glioblastoma tumors to frontline chemotherapy. Our results thus provide rationale for GABPB1L inhibition combined with temozolomide chemotherapy treatment as a promising therapeutic strategy for glioblastoma.Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform–containing complex to the mutant TERT promoter. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM.All study data are included in the article and/or supporting information.