DNA damage response inhibitors enhance tumour treating fields (TTFields) potency in glioma stem-like cells.

Autor: Vanderlinden A; Division of Clinical Medicine, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK., Jones CG; Division of Clinical Medicine, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK., Myers KN; Division of Clinical Medicine, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK., Rominiyi O; Division of Clinical Medicine, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK. o.rominiyi@sheffield.ac.uk.; Division of Neuroscience, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK. o.rominiyi@sheffield.ac.uk.; Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, S10 2JF, UK. o.rominiyi@sheffield.ac.uk., Collis SJ; Division of Clinical Medicine, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK. s.collis@sheffield.ac.uk.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2023 Nov; Vol. 129 (11), pp. 1829-1840. Date of Electronic Publication: 2023 Sep 30.
DOI: 10.1038/s41416-023-02454-0
Abstrakt: Background: High-grade gliomas are primary brain cancers with unacceptably low and persistent survival rates of 10-16 months for WHO grade 4 gliomas over the last 40 years, despite surgical resection and DNA-damaging chemo-radiotherapy. More recently, tumour-treating fields therapy (TTFields) has demonstrated modest survival benefit and been clinically approved in several countries. TTFields is thought to mediate anti-cancer activity by primarily disrupting mitosis. However, recent data suggest that TTFields may also attenuate DNA damage repair and replication fork dynamics, providing a potential platform for therapeutic combinations incorporating standard-of-care treatments and targeted DNA damage response inhibitors (DDRi).
Methods: We have used patient-derived, typically resistant, glioma stem-like cells (GSCs) in combination with the previously validated preclinical Inovitro™ TTFields system together with a number of therapeutic DDRi.
Results: We show that TTFields robustly activates PARP- and ATR-mediated DNA repair (including PARylation and CHK1 phosphorylation, respectively), whilst combining TTFields with PARP1 or ATR inhibitor treatment leads to significantly reduced clonogenic survival. The potency of each of these strategies is further enhanced by radiation treatment, leading to increased amounts of DNA damage with profound delay in DNA damage resolution.
Conclusion: To our knowledge, our findings represent the first report of TTFields applied with clinically approved or in-trial DDRi in GSC models and provides a basis for translational studies toward multimodal DDRi/TTFields-based therapeutic strategies for patients with these currently incurable tumours.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: