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Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer

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Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer Ambber Renee Ward Bachelor of Science (Biomedical) (Honours) Bachelor of Medical Science (Pathology) Bachelor of Psychology (Honours) Bachelor of Behavioural Science A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2020 School of Medicine and QIMR Berghofer Medical Research Institute Abstract Triple negative breast cancer (TNBC) represents 10-20% of all breast cancers and is defined by the absence of estrogen receptors, progesterone receptors and absence of human epidermal growth factor receptor 2 amplification. TNBC is the most aggressive of the subtypes with the poorest prognosis and highest rates of recurrence within 5 years of diagnosis. The standard of care treatment for TNBC is systemic chemotherapy. The development of chemotherapy resistance is a common problem, with relapse rates up to 38% with less than 6 months median survival. Relapse is often associated with aggressive metastatic disease that no longer responds to chemotherapy. RAD51 recombinase is an evolutionarily conserved protein that plays a critical role the homologous recombination (HR) pathway, which faithfully repairs DNA double-strand breaks and damaged replication forks. In normal cells RAD51 expression is tightly regulated and its activity promotes high fidelity repair and genome integrity. However, dysregulation and overexpression of RAD51 is reported in many human malignancies, including TNBC, and is implicated in resistance to DNA damaging radiotherapy, chemotherapy and PARP inhibition and the promotion of tumour progression and metastasis. Wiegmans et al. (2014) identified that RAD51 is required for spontaneous metastasis in TNBC and that RAD51 expression level differentially regulates the expression of several CEBPβ target genes implicated in tumour progression and metastasis. Furthermore, co-immunoprecipitation identified that RAD51 and CEBPβ interact in situ. To elucidate a possible new non-canonical role for RAD51 in transcriptional regulation we set out to gene edit RAD51 with the aim of generating TNBC model cell lines expressing; (1) HR deficient, RAD51 K133R knock-in mutation, (2) RAD51 knockout and (3) CEBPβ knockout. This was a novel approach as RAD51 is required for CRISPR-Cas9 editing and there are no published studies of RAD51 gene editing. RAD51 knock-out was initially successful in MDA-MB-231 cells but could not be stably maintained by cells in culture, likely due to RAD51 being a core fitness gene in this cell line. CEBPβ was successfully knocked out in MDA-MB-231 cells, however difficulty culturing cells from a single cell or at low density prevented isolation of pure clones with CEBPβ knock-out in other TNBC cell lines. We concluded that as an essential cancer gene RAD51 modulation by small molecule inhibition or transient transfection would be more suitable methods for studying RAD51 function in TNBC. i Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer To identify a novel small molecule RAD51 inhibitor we evaluated a library of quinazolinone derivatives and analysed structure activity relationships. Among these compounds we identified compound 17, which binds directly to RAD51. We hypothesized that inhibiting RAD51 in TNBC cell lines would block repair by HR, thereby sensitising tumour cells to DNA damaging irradiation and chemotherapy. We found that compound 17 inhibits HR in MDA-MB-231 cells by ~7-fold. Compared to the base compound (B02), compound 17 exhibited up to ~8-fold improved growth inhibition in a panel of TNBC cell lines and 2.5-fold increased inhibition of DNA damage-induced RAD51 foci formation. Additionally, compound 17 significantly enhanced sensitivity to DNA damaging radiotherapy and chemotherapies, suggesting a potentially targeted therapy for TNBC. A known mechanism by which cancer cells acquire chemoresistance is by deregulation of the DNA damage response, a process that can also create dependencies on specific DNA repair pathways. The clinical success of PARP inhibitors in BRCA mutant TNBC highlights the potential of targeting these dependencies therapeutically to induce synthetic lethality. Understanding DNA repair deficiencies is therefore vital for appropriate therapeutic choices. This is clinically utilised with homologous recombination deficiency (HRD) scoring based on TNBC mutational load, with a positive HRD status predicting PARP inhibition- mediated synthetic lethality. While genetic instability provides a snapshot of deregulated DNA damage response that drives chemotherapy resistance, we have analysed the functional consequences of repair deregulation. Here we show adaption to frontline TNBC chemotherapy combination doxorubicin and docetaxel. We find that chemoresistance results in enhanced genome instability, reliance upon DNA repair mediated by RAD51 and changes in gene expression profile guided by c-ABL and p73 and loss of p53 and BRCA1. Further we find that targeting RAD51 with our small molecule inhibitor can resensitize cells to docetaxel and doxorubicin and overcome DNA damage induced chemoresistance. ii Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. iii Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer Publications included in this thesis No publications included. Submitted manuscripts included in this thesis No manuscripts submitted for publication. Other publications during candidature Ivanova, E., Ward, A., Wiegmans, A. P., & Richard, D. J. (2020). Circulating Tumour Cells in Metastatic Breast Cancer: From genome instability to metastasis. Frontiers in Molecular Biosciences, 7, 134. Ward, A., Dong, L., Harris, J. M., Khanna, K. K., Al-Ejeh, F., Fairlie, D. P., Liu, L. (2017). Quinazolinone derivatives as inhibitors of homologous recombinase RAD51. Bioorganic and Medicinal Chemistry Letters, 27(14), 3096-3100. Wiegmans, A. P., Yap, P.-Y., Ward, A., Lim, Y. C., & Khanna, K. K. (2015). Differences in expression of key DNA damage repair genes after epigenetic-induced BRCAness dictate synthetic lethality with PARP1 inhibition. Molecular Cancer Therapeutics, 14(10), 2321-2331. Manuscripts in preparation Wiegmans, A. P., Ward, A., Ivanova, E., Van Oosetrhout, R., Nones, K., Sadowski, M., Kelly, G., Morrical, S., Lee, J. S., and Richard, D (2020). c-ABL drives frontline chemotherapy chemoresistance via DNA repair crisis and switch to homologous recombination repair in triple negative breast cancer. Contributions by others to the thesis Dr Ligong Liu and Lilong Dong (Universitiy of Queensland, Institute of Molecular Biosciences) synthesised the quinazolinone compounds described in Chapter 4 Results 4.2.2 and depicted in Figures 4.3 and 4.4.. Dr Johnathan Harris (School of Life Science, Queensland University of Technology) In- silico docking study for RAD51 inhibitor optimisation described in Chapter4 Results 4.2.1 and depicted in Figure 4.2. Dr Katia Nones (Medical Genomics Laboratory, QIMR Berghofer) conducted SNP array analysis described in chapter 5 Results 5.2 and depicted in Figures 5.5C-D, 5.5D-H. iv Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer Ekaterina Ivanova and Romy Van Oosetrhout (Tumour Microenvironment Laboratory, QIMR Berghofer) assisted with western blots depicted in Chapter 3 Results, Figures 3.7 and 3.8. Statement of parts of the thesis submitted to qualify for the award of another degree No works submitted towards another degree have been included in this thesis. Research Involving Human or Animal Subjects No animal or human subjects were involved in this research. v Investigating Molecular Targets of the DNA Damage Response in Triple Negative Breast Cancer Acknowledgements I am grateful to Dr Jason Lee
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