KINOME-WIDE SYNTHETIC LETHAL SCREEN IDENTIfiES PANK4 AS A MODULATOR OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 26; no. Supplement_7; p. vii5
• Main Authors: Vella, Dr Viviana, Ditsiou, Dr Angeliki, Chalari, Dr Anna, Eravci, Dr Murat, Wooller, Dr Sarah K, Gagliano, Prof Teresa, Bani, Ms Cecilia, Kerschbamer, Dr Emanuela, Karakostas, Mr Christos, Xu, Dr Bin, Zhang, Dr Yongchang, Pearl, Dr Frances M G, Lopez, Dr Gianluca, Peng, Dr Ling, Stebbing, Prof Justin, Klinakis, Prof Apostolos, Giamas, Prof Georgios
• Format: Journal Article
• Language: English
• Published: 15.10.2024
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noae158.017

Abstract AIMS Temozolomide (TMZ) represents the cornerstone of glioblastoma (GBM) therapy. However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterised. We aimed to uncover synthetic lethal partners of TMZ in GBM that could enhance the effect of TMZ, thus improving TMZ therapy response. METHOD A kinome-wide RNAi screen was performed in a TMZ-resistant GBM cell model. A panel of several TMZ-resistant and patient-derived GBM cell lines was implemented for in vitro validation of our findings through several phenotypic assays. In vivo TMZ-resistant GBM xenografts and immunohistochemical (IHC) analysis of IDH- wildtype GBM specimens were employed to assess the clinical relevance of our findings. Tandem Mass Tag (TMT)-based quantitative proteomic studies were undertaken to elucidate the underlying mechanisms. RESULTS Following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) was uncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborated the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. A Tandem Mass Tag (TMT)-based quantitative proteomic approach revealed that PANK4 abrogation leads to a significant downregulation of numerous proteins with central roles in cellular detoxification and cellular response to oxidative stress. Mechanistically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. CONCLUSION Our study provides novel insights into chemoresistance in GBM and unveils a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM.