Leiden University Scholarly Publications

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Barazas, M. (2021)

Cancer chess: molecular insights into PARP inhibitor resistance

Doctoral Thesis
The clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double-strand break (DSB) repair pathway homologous recombination (HR) – results in a remarkable sensitivity to PARP1 inhibition (PARPi). Despite spectacular initial responses in patients, resistance to PARPi treatment may develop and must be overcome to maximally exploit this interaction in the clinic. Genetically engineered (mouse) model systems have shown that PARPi resistance may arise through inactivation of the 53BP1 pathway. The 53BP1 pathway normally protects DSB ends from resection and the removal of this “brake” restores HR in the absence of BRCA1. However, how the 53BP1 pathway protects DSB ends from resection has remained elusive. In this thesis, advances in 3D tumor organoid culture protocols and CRISPR/Cas9 (screening) technology were applied to identify and validate new components...Show moreThe clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double-strand break (DSB) repair pathway homologous recombination (HR) – results in a remarkable sensitivity to PARP1 inhibition (PARPi). Despite spectacular initial responses in patients, resistance to PARPi treatment may develop and must be overcome to maximally exploit this interaction in the clinic. Genetically engineered (mouse) model systems have shown that PARPi resistance may arise through inactivation of the 53BP1 pathway. The 53BP1 pathway normally protects DSB ends from resection and the removal of this “brake” restores HR in the absence of BRCA1. However, how the 53BP1 pathway protects DSB ends from resection has remained elusive. In this thesis, advances in 3D tumor organoid culture protocols and CRISPR/Cas9 (screening) technology were applied to identify and validate new components of the 53BP1 pathway that render BRCA1 deficient cells resistant to PARPi upon their loss. Furthermore, a new acquired vulnerability that can be therapeutically exploited to deplete such PARPi resistant cells is described. Together, this thesis provides mechanistic insight in DSB repair and illustrates how such fundamental knowledge may stand at the basis to combat resistance.
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BRCA1
Breast cancer
PARP inhibitor
HR deficient
53BP1 pathway
CST complex
SHLD complex
DNA end resection
Drug resistance
Genetically engineered mouse model
All authors
Barazas, M.
Supervisor
Jonkers, J.M.M.; Rottenberg, S.
Committee
Irth, H.; Bouwstra, J.A.; Attikum, H. van; Noordermeer, S.M.; Vugt, M. van
Qualification
Doctor (dr.)
Awarding Institution
Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
Date
2021-12-14
ISBN (print)
9789464193664

Funding

Sponsorship
The research described in this thesis was performed at the Division of Molecular Pathology of the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI-AVL) and Oncode Institute, Amsterdam, The Netherlands, and was financially supported by the Dutch Cancer Society (KWF 2011-5220 and 2014-6532 to S. Rottenberg and J. Jonkers), the Netherlands Organization for Scientific Research (VICI 91814643, NGI 93512009, Cancer Genomics Netherlands, and a National Roadmap Grant for Large-Scale Research Facilities to J. Jonkers), the Swiss National Science Foundation (310030_179360 to S. Rottenberg), the Swiss Cancer League (KLS-4282-08-2017 to S. Rottenberg); and the European Union (ERC CoG-681572 to S. Rottenberg and ERC Synergy Grant 319661 to J. Jonkers).