KDM5B predicts temozolomide-resistant subclones in glioblastoma

Vivien Ullrich; Sarah Ertmer; Anna Baginska; Madeleine Dorsch; Hanah H Gull; Igor Cima; Pia Berger; Celia Dobersalske; Sarah Langer; Loona Meyer; Philip Dujardin; Sied Kebir; Martin Glas; Tobias Blau; Kathy Keyvani; Laurèl Rauschenbach; Ulrich Sure; Alexander Roesch; Barbara M Grüner; Björn Scheffler

doi:10.1016/j.isci.2023.108596

KDM5B predicts temozolomide-resistant subclones in glioblastoma

iScience. 2023 Dec 3;27(1):108596. doi: 10.1016/j.isci.2023.108596. eCollection 2024 Jan 19.

Authors

Vivien Ullrich^{1

2

3

4}, Sarah Ertmer^{1

2

3

4}, Anna Baginska^{1

2

3

5}, Madeleine Dorsch^{2

3

5}, Hanah H Gull^{1

3

6

7}, Igor Cima^{1

2

3

4}, Pia Berger^{1

2

3

4}, Celia Dobersalske^{1

2

3

4}, Sarah Langer^{1

2

3

4}, Loona Meyer^{1

2

3

4}, Philip Dujardin^{2

3

5}, Sied Kebir^{1

2

3

7

8}, Martin Glas^{1

2

3

7

8}, Tobias Blau⁹, Kathy Keyvani⁹, Laurèl Rauschenbach^{1

2

3

6

7}, Ulrich Sure^{2

3

6

7}, Alexander Roesch^{2

3

10

11}, Barbara M Grüner^{2

3

5

11}, Björn Scheffler^{1

2

3

4

11}

Affiliations

¹ DKFZ-Division Translational Neurooncology at the WTZ, DKTK partner site, University Hospital Essen, 45147 Essen, Germany.
² German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between DKFZ and University Hospital Essen, Germany.
³ West German Cancer Center (WTZ), University Hospital Essen, 45147 Essen, Germany.
⁴ German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
⁶ Department of Neurosurgery and Spine Surgery, University Hospital Essen, 45147 Essen, Germany.
⁷ Center for Translational Neuroscience and Behavioral Science (C-TNBS), University of Duisburg-Essen, 45147 Essen, Germany.
⁸ Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, 45147 Essen, Germany.
⁹ Department of Neuropathology, University Hospital Essen, 45147 Essen, Germany.
¹⁰ Department of Dermatology, University Hospital Essen, 45147 Essen, Germany.
¹¹ Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany.

Abstract

Adaptive plasticity to the standard chemotherapeutic temozolomide (TMZ) leads to glioblastoma progression. Here, we examine early stages of this process in patient-derived cellular models, exposing the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion. By integration of a reporter, we show its preferential activity in rare, stem-like ALDH1A1+ cells, immediately increasing expression upon TMZ exposure. Naive, genetically unmodified KDM5B^high cells phosphorylate AKT (pAKT) and act as slow-cycling persisters under TMZ. Knockdown of KDM5B reverses pAKT levels, simultaneously increasing PTEN expression and TMZ sensitivity. Pharmacological inhibition of PTEN rescues the effect. Interference with KDM5B subsequent to TMZ decreases cellular vitality, and clonal tracing with DNA barcoding demonstrates high individual levels of KDM5B to predict subclonal expansion already before TMZ exposure. Thus, KDM5B^high treatment-naive cells preferentially contribute to the dynamics of drug resistance under TMZ. These findings may serve as a cornerstone for future biomarker-assisted clinical trials.

Keywords: Cancer; Cell biology; Health sciences; Pharmacology.