THESIS
2014
iv leaves, v-xiv, 108 pages : illustrations (some color) ; 30 cm
Abstract
Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. Radiotherapy is the
primary approach for NPC treatment. However, activating the ATR-CHK1-WEE1 axis with
ionizing radiation alone imposes limited cytotoxicity and remains inadequate for advanced
stages of the disease. Recently, a number of small-molecule inhibitors of ATR, CHK1 and
WEE1 are being evaluated in clinical trials with the major focus to potentiate cytotoxicity of
DNA-damaging agents.
In this study, I demonstrated that pharmacological inactivation of WEE1 (MK-1775),
CHK1 (AZD7762) or ATR (VE-821) abrogated the G
2 DNA damage checkpoint in irradiated
NPC cells. Although abrogation of the checkpoint induced untimely mitosis, this did not offer
additional synergism with irradiation in inducing cytotoxi...[
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Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. Radiotherapy is the
primary approach for NPC treatment. However, activating the ATR-CHK1-WEE1 axis with
ionizing radiation alone imposes limited cytotoxicity and remains inadequate for advanced
stages of the disease. Recently, a number of small-molecule inhibitors of ATR, CHK1 and
WEE1 are being evaluated in clinical trials with the major focus to potentiate cytotoxicity of
DNA-damaging agents.
In this study, I demonstrated that pharmacological inactivation of WEE1 (MK-1775),
CHK1 (AZD7762) or ATR (VE-821) abrogated the G
2 DNA damage checkpoint in irradiated
NPC cells. Although abrogation of the checkpoint induced untimely mitosis, this did not offer
additional synergism with irradiation in inducing cytotoxicity in NPC cells.
In the absence of DNA damage, targeting WEE1 or CHK1 promoted bypass of the G
2
DNA damage checkpoint, mitotic entry and cell death, as characterized by the
dephosphorylation of CDK1
Tyr15, phosphorylation of histone H3
Ser10, and induction on PARP
cleavage. In comparison to the immortalized normal nasopharyngeal epithelial cells, NPC cell
overexpressed the ATR-CHK1-WEE1 axis and were more sensitive to WEE1 and CHK1
inactivation. Unexpectedly, partial inhibition of WEE1 has the effect of accelerating cell cycle
and thereby increasing cell proliferation. This potential limitation of the inhibitors could be
overcome by targeting WEE1 and CHK1 simultaneously.
My results provide basis of combining WEE1 and CHK1 inhibition in developing target
therapy for NPC.
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