Targeting Wee1-like protein kinase to treat cancer.
New anticancer agents are needed in order to overcome the resistance of cancer cells to standard chemotherapy. At present, many of the molecular events that drive the malignant transformation and progression have been identified and there is optimism that the development of agents that specifically target such events will improve treatment outcomes. Cancer cells present common alterations in components of pathways that are involved in the normal cell cycle regulation and in mechanisms of DNA damage repair. Wee1-like protein kinase is a tyrosine kinase with a key role as an inhibitory regulator of the G2/M checkpoint that precedes entry into mitosis. Abrogation of this checkpoint through Wee1 inhibition may result in increased antitumor activity of agents that cause DNA damage such as radiation therapy or some cytotoxic agents. This has been confirmed in preclinical studies and results of clinical studies evaluating a Wee1 inhibitor are awaited to establish its activity in combination with chemotherapy. Here we review the role of Wee1 tyrosine kinase in the control of the G2/M checkpoint and the effects of G2/M checkpoint abrogation through Wee1 inhibition. We present results of preclinical studies with Wee1 inhibitors and the results of the first clinical trial recently reported, evaluating MK-1775, a small-molecule inhibitor of Wee1.
Stathis
Anastasios
A
Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, and University of Toronto, Toronto, Ontario, Canada.
Oza
Amit
A
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology; D011744:Pyrimidinones
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib