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 G₂ 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...[ Read more ]

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 G₂ 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 G₂ 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.