Hematologic malignancies,including leukemia,lymphoma,and multiple myeloma,are hazardous diseases characterized by the uncontrolled proliferation of cancer cells.Dysregulated cell cycle resulting from genetic and epige...Hematologic malignancies,including leukemia,lymphoma,and multiple myeloma,are hazardous diseases characterized by the uncontrolled proliferation of cancer cells.Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events.Importantly,cyclin-dependent kinases(CDKs),complexed with their functional partner cyclins,play dominating roles in cell cycle control.Yet,efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes.Recently,mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase(WEE1)to modulate CDK activity,and correspondingly,a variety of therapeutic inhibitors have been developed to achieve clinical benefits.Thus,WEE1 may become a promising target to modulate the abnormal cell cycle.However,its function in hematologic diseases remains poorly elucidated.In this review,focusing on hematologic malignancies,we describe the biological structure of WEE1,emphasize the latest reported function of WEE1 in the carcinogenesis,progression,as well as prognosis,and finally summarize the therapeutic strategies by targeting WEE1.展开更多
Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises...Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises from tumor protein p53(p53)alterations and loss of cell cycle control.However,the role of p53 status in GIST therapeutic potential has rarely been studied,so this study aimed to employ both wild-type andmutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.Methods:The efficacy of the mouse double minute 2 homolog(MDM2)inhibitor(HDM201)and the Wee1 G2 checkpoint kinase(Wee1)inhibitor(adavosertib)was confirmed in both p53 wild-type(p53 WT)and p53 mutant(p53 MT)GIST cells.The anti-proliferative effects were assessed using the Cell Counting Kit-8(CCK-8)assay.Flow cytometry(FACS)and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy.These findings were further validated in a xenograft model.Results:HDM201 selectively inhibited growth and triggered apoptosis in p53WT GIST cells,while adavosertib was effective mainly in p53 MT cells.Western blot analysis revealed thatHDM201 increased p53 and p21 levels in p53WT cells,and adavosertib affectedWee1 and phospho-cdc2 expression in both p53WT and p53 MT cells.In a xenograft mouse model,HDM201 significantly reduced the tumor volume and weight in p53WTGIST cells,whereas p53MT tumors showed only a moderate size reduction with adavosertib,without significant changes.Conclusions:Our results highlight the importance of p53 status in guiding GIST treatment.p53 WT tumors respond toMDM2 inhibitors,while p53 MTtumors show greater sensitivity toWee1 inhibitors,supporting p53 pathway targeting as a promising strategy for GIST patients.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81920108004,82270127,82203880)the Hunan Provincial Natural Science Foundation of China(No.2023JJ30928,2024JJ3037)+2 种基金the Changsha Municipal Natural Sci-Science Foundation(No.kq2208382)the Fellowship of the China Postdoctoral Science Foundation(No.2023T160740)the Hunan Province Clinical Medical Technology Innovation Guidance Project(No.2021SK50917,2023SK4056)。
文摘Hematologic malignancies,including leukemia,lymphoma,and multiple myeloma,are hazardous diseases characterized by the uncontrolled proliferation of cancer cells.Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events.Importantly,cyclin-dependent kinases(CDKs),complexed with their functional partner cyclins,play dominating roles in cell cycle control.Yet,efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes.Recently,mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase(WEE1)to modulate CDK activity,and correspondingly,a variety of therapeutic inhibitors have been developed to achieve clinical benefits.Thus,WEE1 may become a promising target to modulate the abnormal cell cycle.However,its function in hematologic diseases remains poorly elucidated.In this review,focusing on hematologic malignancies,we describe the biological structure of WEE1,emphasize the latest reported function of WEE1 in the carcinogenesis,progression,as well as prognosis,and finally summarize the therapeutic strategies by targeting WEE1.
基金financially supported by grants from the Chang-Gung Memorial Hospital(CMRPG3J0971~3,CMRPVVP0111,and CMRPVVQ0041 to CEWCMRPG3P0101 to HJS)the National Science and Technology Council(113-2628-B-182-001-MY3 and 113-2811-B-182-024 to CEW).
文摘Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises from tumor protein p53(p53)alterations and loss of cell cycle control.However,the role of p53 status in GIST therapeutic potential has rarely been studied,so this study aimed to employ both wild-type andmutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.Methods:The efficacy of the mouse double minute 2 homolog(MDM2)inhibitor(HDM201)and the Wee1 G2 checkpoint kinase(Wee1)inhibitor(adavosertib)was confirmed in both p53 wild-type(p53 WT)and p53 mutant(p53 MT)GIST cells.The anti-proliferative effects were assessed using the Cell Counting Kit-8(CCK-8)assay.Flow cytometry(FACS)and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy.These findings were further validated in a xenograft model.Results:HDM201 selectively inhibited growth and triggered apoptosis in p53WT GIST cells,while adavosertib was effective mainly in p53 MT cells.Western blot analysis revealed thatHDM201 increased p53 and p21 levels in p53WT cells,and adavosertib affectedWee1 and phospho-cdc2 expression in both p53WT and p53 MT cells.In a xenograft mouse model,HDM201 significantly reduced the tumor volume and weight in p53WTGIST cells,whereas p53MT tumors showed only a moderate size reduction with adavosertib,without significant changes.Conclusions:Our results highlight the importance of p53 status in guiding GIST treatment.p53 WT tumors respond toMDM2 inhibitors,while p53 MTtumors show greater sensitivity toWee1 inhibitors,supporting p53 pathway targeting as a promising strategy for GIST patients.
