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Wang, Taixiang

University of British Columbia

Inhibition of DNA-PK disrupts the repair of DNA double strand breaks (DSBs) through non-homologous end-joining (NHEJ), making tumour cells more susceptible to DNA-damaging agents. This thesis explores the underlying mechanisms as well as target cell populations of DNA damaging agents when they are combined with DNA-PK inhibitors, particularly Topoisomerase II (Top2) poisons and radiotherapy. The results confirmed that DNA-PK inhibitors + Top2 poisons is a potent combination that increased the cell kill both in vitro and in vivo. Flow cytometry and immunofluorescent staining results further showed amplified DNA damage not only in the proliferating cells, but also in non-proliferative though transcriptionally active cells. This broadening of the target population of a DNA-damaging anti-cancer treatment by DNA-PK inhibitors was also seen with radiation in breast cancer type 1 or type 2 susceptibility protein (BRCA1/2) deficient tumour cells. In vitro and in vivo evaluation of cell survival both demonstrated greater radiosensitizing effects of DNA-PK inhibitors in BRCA1/2 deficient cells relative to a Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor that has a well-established synthetic lethal effect in these cells. Compared with the PARP inhibitor, DNA-PK inhibitors have a greater anti-cancer effect due to their wider scope of activity, sensitizing both proliferating and non-proliferating tumour cells to radiation treatment. However, the targeting of non-proliferating cells with DNA-PK inhibitors also posed a significant survival challenge to normal tissue cells, as increased in vivo toxicity was observed in the treatment groups for both Top2 poisons and radiation treatment when combined with DNA-PK inhibitors. These findings demonstrate the importance of validating target cell population of anti-cancer treatments, including for novel combinations when the affected cells and activity mechanisms for individual treatments might already be established. The implications are significant for DNA-PK inhibitors, already in clinical trials in combination with Top2 poisons and radiation where dose-limiting toxicity has already limited the scope of clinical benefit. The moderate to severe toxicity observed in mice treated with DNA damaging agents in combination with DNA-PK inhibitors suggests that a tumour-specific targeting strategy and careful dosage design is required to minimize adverse effects in normal tissues and achieve clinical benefits.

Text

2024-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88125

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/