PD0166285 sensitizes esophageal squamous cell carcinoma to radiotherapy by dual inhibition of WEE1 and PKMYT1

Abstract

BackgroundEsophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a 5-year survival rate of only 20%. More than 80% of ESCC patients possess TP53 mutation, which abolishes the G1/S checkpoint and accelerates the cell cycle. Thus, WEE1 and PKMYT1, regulators of G2/M phase in cell cycle, play essential roles in TP53-mutated cancer cells. PD0166285(PD) is a pyridopyrimidine compound that can inhibit WEE1 and PKMYT1 simultaneously, however, the effects of PD on ESCC, either as monotherapy or in combination therapy with radiotherapy, remain unclear.MethodsTo measure the anti-tumor efficacy of PD in ESCC cells, cell viability, cell cycle and cell apoptosis assays were examined in KYSE150 and TE1 cells with PD treatment. The combination therapy of PD and irradiation was also performed in ESCC cells to find whether PD can sensitize ESCC cells to irradiation. Vivo assays were also performed to investigate the efficacy of PD.ResultsWe found that the IC50 values of PD among ESCC cells ranged from 234 to 694 nM, PD can regulate cell cycle and induce cell apoptosis in ESCC cells in a dose-dependent manner. When combined with irradiation, PD sensitized ESCC cells to irradiation by abolishing G2/M phase arrest, inducing a high ratio of mitosis catastrophe, eventually leading to cell death. We also demonstrated that PD can attenuate DNA damage repair by inhibiting Rad51, further research also found the interaction of WEE1 and Rad51. In vivo assays, PD inhibited the tumor growth in mice, combination therapy showed better therapeutic efficacy.ConclusionPD0166285 can exert antitumor effect by inhibiting the function of WEE1 and PKMYT1 in ESCC cells, and also sensitize ESCC cells to irradiation not only by abolishing G2/M arrest but also attenuating DNA repair directly. We believe PD0166285 can be a potent treatment option for ESCC in the future.

Suit the Remedy to the Case: An Activatable DNA Damage Initiator for Postsurgical Therapy of Glioblastoma with TP53 Mutations

“…Fortunately, TP53-mutant tumor cells highly rely on the G2/M checkpoint of the cell cycle because of the compromised G1/S checkpoint, therefore providing a marvelous opportunity for the treatment of tumors carrying TP53 mutations. , As the main members of the WEE kinase family, WEE1 and PKMYT1 both play a key role in the cell cycle for restoring inherent DNA damage during the replication process or induced DNA damage by external stimuli. − Concretely, WEE1 and PKMYT1 together inhibit the activity of cyclin-dependent kinase 1 (CDK1) through phosphorylating CDK1 at threonine 14 (Thr14) and tyrosine 15 (Tyr15) to activate G2/M checkpoint, which arrests the cell cycle to timely repair damaged DNA before entering into mitosis. , The simultaneous suppression of WEE1 and PKMYT1 can trigger a sustained formation of CDK1-cyclin B1 complex to prematurely terminate G2/M checkpoint, which leads to the disturbance of the cell cycle and an eventual freedom of DNA damage in TP53-mutant tumor cells. − Thus, WEE1 and PKMYT1 can promisingly serve as the customized targets for treating GBM with TP53 mutations . As the sole dual-targeted inhibitor of WEE1 and PKMYT1 at the moment, PD0166285 (PD) has shown an admirable antitumor efficacy, but its application in GBM with TP53 mutations is rarely reported. , …”