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Inhibiting the DNA damage response in mitosis to kill BRCA1/2-deficient cancer cells

LEAD SUPERVISOR:  Dr Andrew Blackford, Department of Oncology

Co-supervisor: Dr Ross Chapman, Nuffield Department of Medicine

Commercial partner: AstraZeneca, Cambridge

 

Many tumour cells are deficient in one or more DNA damage response pathways, making them overly reliant on the ones they have left. This can make such cells particularly vulnerable in the clinic to small molecule inhibitors that target DNA repair enzymes. Therapies that exploit this concept of synthetic lethality are perhaps best exemplified by the use of PARP inhibitors such as olaparib/Lynparza to target cancers that are deficient in the homologous recombination DNA repair pathway due to loss of the tumour suppressors BRCA1 or BRCA2. However, many cancers can rapidly become resistant to PARP inhibitors, meaning that there is an increasing need to develop strategies to overcome this resistance in the clinic.

Emerging evidence suggests that BRCA-deficient cells are particularly reliant for their survival on a complex containing two proteins called TOPBP1 and CIP2A, which we and others recently discovered can form filamentous structures that appear to bridge broken chromosome ends if they are damaged during mitosis1–3. We hypothesise that 1) the TOPBP1-CIP2A complex acts as a molecular “sticking plaster” to hold broken chromosomes together during mitosis until DNA double-strand break repair pathways are switched back on in the following G1 phase; and 2) that because BRCA-deficient cells often accumulate DNA damage during replication that can be carried over into mitosis, they require TOPBP1-CIP2A to prevent catastrophic chromosome shattering during cell division.

Importantly, BRCA-deficient cells that have acquired resistance to PARP inhibition are still reliant on the TOPBP1-CIP2A complex for their survival2. This suggests that inhibiting TOPBP1-CIP2A may be an effective strategy to target PARP inhibitor resistance in the clinic. Although TOPBP1 and CIP2A are not obvious drug targets themselves, we have preliminary data to indicate that their interaction is at least partly phospho-dependent. This indicates that there must exist an as-yet unidentified kinase that regulates TOPBP1-CIP2A complex formation, and which therefore is a potential drug target to kill BRCA-deficient cells—including at those that have become resistant to PARP inhibitors.

The aim of this DPhil project will be to characterise the TOPBP1-CIP2A complex further at the molecular level, and to identify how it is regulated in cells. In doing so, we hope to identify a kinase as a novel drug target to overcome PARP inhibitor resistant BRCA-deficient cancer cells. The project is therefore highly relevant to MRC remit, particularly to the “Precision Medicine” strategic priority. The project is also of strategic importance to AstraZeneca, because their PARP inhibitor olaparib (Lynparza) is the first such compound to be approved and they therefore have a strong interest in identifying mechanisms of drug resistance and new ways it can be overcome. The primary supervisor’s lab (Blackford) first discovered the importance of the TOPBP1 protein for the DNA damage response in mitosis1, and the second supervisor’s lab (Chapman) discovered key mechanisms of PARP inhibitor resistance in BRCA-deficient cells4,5. Both labs therefore have a keen interest in the subject of this project, and have successfully collaborated previously on multiple projects5,6.

 

1. Leimbacher, P.-A. et al. MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis. Mol. Cell 74, 571-583 (2019).

2. Adam, S. et al. CIP2A is a prime synthetic-lethal target for BRCA-mutated cancers. bioRxiv (2021) doi:10.1101/2021.02.08.430060.

3. Zompit, M. D. M. et al. The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis. bioRxiv (2021) doi:10.1101/2021.02.08.430274.

4. Ghezraoui, H. et al. 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 560, 122–127 (2018).

5. Becker, J. R. et al. The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nature Commun. 9, 5406 (2018).

6. Polo, S. E. et al. Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair. Mol. Cell 45, 505–516 (2012).

 

Apply using course: DPhil in Oncology

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