Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Abstract

Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

“…Hence, simultaneous inhibition of WEE1 and CHK1 is a promising strategy. , Inhibition of ATR, the upstream regulator of CHK1, with WEE1, also elevates cytotoxicity due to elevated replication stress in acute myeloid leukemia (AML) and triple-negative breast cancer (TNBC), in addition to the antimetastatic effect. Thus, clinical trials ( NCT03330847 ) using combination therapies provide a therapeutic advantage due to the lower toxicity profile of ATR inhibitors (ATRi) compared to CHK1 inhibitors (CHK1i). − However, this combination has dissimilar effects on different cancer cells; hence, further development may be restricted . Inhibiting WEE1 and RAD51 (responsible for repairing double-strand breaks of DNA) together also offers increased genotoxicity in a similar mechanism …”

Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR

“…A recent study suggest higher copy number of CCNE1 predicts higher sensitivities of high grade serous ovarian cancer to combination of WEE1 and ATR1 [ 77 ]. Whereas, synergy effect in the combination of ATR inhibitor and WEE1 inhibitor is found in both high CCNE1-expressing osteosarcoma cell line and low CCNE1-expressing lung cancer cell lines [ 78 ]. Prior studies show ~ 20% OCCC had CCNE1 copy number gain and overexpression and are associated with poor prognosis [ 79 , 80 ].…”

Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells

“…Of note is that the higher inhibitor concentrations are toxic even without irradiation, and the concentrations typically used for radiosensitization of cancer cell lines are closer to the lower concentrations in our study. Radiosensitizing effects have for instance been reported with 25-50 nM VE822 in U2OS and A549 cells ( 40 ) and with 100-300 nM AZD6738 in A549 and H460 cells ( 41 ), as measured by clonogenic survival. Interestingly, in order to cause pronounced increases in IFN signaling, the cells required higher concentrations of the inhibitors than what is needed for a mere radiosensitizing effect.…”