2. Academic Validation
  3. Kinome-Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma

Kinome-Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma

  • Adv Sci (Weinh). 2024 Feb 14:e2306027. doi: 10.1002/advs.202306027.
Viviana Vella 1,  Angeliki Ditsiou 1,  Anna Chalari 2,  Murat Eravci 1,  Sarah K Wooller 3,  Teresa Gagliano 4,  Cecilia Bani 1,  Emanuela Kerschbamer 4,  Christos Karakostas 2,  Bin Xu 5,  Yongchang Zhang 6,  Frances M G Pearl 3,  Gianluca Lopez 7 8,  Ling Peng 9,  Justin Stebbing 10,  Apostolos Klinakis 2,  Georgios Giamas 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
  • 2 Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece.
  • 3 School of Life Sciences, Bioinformatics Group, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
  • 4 Department of Medicine, University of Udine, Udine, 33100, Italy.
  • 5 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430064, China.
  • 6 Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 430064, China.
  • 7 Division of Pathology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, 20122, Italy.
  • 8 Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, 20122, Italy.
  • 9 Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310003, China.
  • 10 Department of Life Sciences, Anglia Ruskin University, East Road, Cambridge, CB1 1PT, UK.
PMID: 38353396 DOI: 10.1002/advs.202306027
Abstract

Temozolomide (TMZ) represents the cornerstone of therapy for glioblastoma (GBM). 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 characterized. Here, following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) isuncovered 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, corroborates 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. Furthermore, a Tandem Mass Tag (TMT)-based quantitative proteomic approach, reveals that PANK4 abrogation leads to a significant downregulation of a host of proteins with central roles in cellular detoxification and cellular response to oxidative stress. More specifically, 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. Collectively, a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM is unveiled.

Keywords

DUF89 domain; GBM; PANK4; TMT-based quantitative proteomics; TMZ resistance; cellular detoxification; kinome-wide RNAi screen.

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