THESIS
2017
xviii, 139 pages : illustrations (some color) ; 30 cm
Abstract
Nasopharyngeal carcinoma is an aggressive head and neck cancer with high prevalence in
southern China, including Hong Kong. Despite the high initial response rate to radiotherapy,
treatment failure is often resulted from distant metastases in the advanced disease. As
standard radiotherapy and chemoradiotherapy induce DNA damage, I investigated whether
uncoupling the DNA damage response pathway could sensitize this cancer type.
The potential of sensitizing irradiated cells via inhibition of the G
2 DNA damage checkpoint
was first examined. The G
2 DNA damage checkpoint is controlled by the ATM/ATR-CHK1/2-
WEE1 axis of protein kinases. I demonstrated that radiosensitization could be achieved by
bypassing the ionizing radiation-induced G
2 DNA damage checkpoint using a WEE1 inhibitor...[
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Nasopharyngeal carcinoma is an aggressive head and neck cancer with high prevalence in
southern China, including Hong Kong. Despite the high initial response rate to radiotherapy,
treatment failure is often resulted from distant metastases in the advanced disease. As
standard radiotherapy and chemoradiotherapy induce DNA damage, I investigated whether
uncoupling the DNA damage response pathway could sensitize this cancer type.
The potential of sensitizing irradiated cells via inhibition of the G
2 DNA damage checkpoint
was first examined. The G
2 DNA damage checkpoint is controlled by the ATM/ATR-CHK1/2-
WEE1 axis of protein kinases. I demonstrated that radiosensitization could be achieved by
bypassing the ionizing radiation-induced G
2 DNA damage checkpoint using a WEE1 inhibitor
(MK-1775). However, bypassing the checkpoint via inhibition of CHK1 or ATR failed to enhance
cell death. Intriguingly, I found that ATM was dispensable for both the activation and
maintenance of the G
2 DNA damage checkpoint. Further experiments revealed that mitotic
catastrophe could be induced with the co-inhibition of WEE1 and CHK1 in unirradiated cells.
The capacity of sensitizing cells via inhibition of the major DNA double strand break (DSB)
repair pathways was also studied. Eukaryotic cells repair DNA DSBs mainly via non-homologous
end-joining (NHEJ), homologous recombination repair (HRR), and a backup
pathway called alternative-NHEJ (alt-NHEJ). Inhibition of alt-NHEJ in a HRR-deficient
background was proved to be synthetic lethal. I demonstrated that HRR-deficiency could be
induced via ATM inhibition. The co-inhibition of HRR and alt-NHEJ via the inhibition of ATM
and PARP1 resulted in the accumulation of DNA DSBs, activation of the G
2 DNA damage
checkpoint, and reduced cell proliferation.
These studies revealed that radiosensitization of nasopharyngeal carcinoma could be achieved
by checkpoint bypass in irradiated cells, the co-inhibition of G
2 DNA damage checkpoint
components, or the co-inhibition of major DNA DSB repair pathways.
(294 words)
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