HKUMed identifies this human enzyme as a potential therapeutic target for acute leukemia
A research team, led by Professor Anskar Leung Yu-hung from the Department of Medicine at the School of Clinical Medicine, LKS Faculty of Medicine, University of Hong Kong (HKUMed), has pinpointed polo-like kinase 4 (PLK4) as a promising therapeutic target for acute myeloid leukemia (AML) cases carrying the TP53 mutation. AML is a devastating disease with limited effective treatment options available at present. The team’s findings hold potential in laying the groundwork for clinical trials aimed at enhancing patient outcomes within this specific AML subtype.
AML is a type of blood cancer caused by genetic changes in blood stem cells in bone marrow. Its symptoms include fever, bleeding and infection. Without treatment, AML patients may deteriorate rapidly and die. Conventional treatments include intensive chemotherapy and blood stem cell transplantation.
Overall, only 40% of patients can be cured and enjoy long-term survival. A subtype of AML, carrying a mutation of a tumour suppressive gene, known as TP53, responds poorly to conventional treatment, resulting in a high mortality rate within a year after diagnosis. At present, there is no specific
treatment available for this AML subtype, underscoring the urgent need to develop novel and specific therapies for this disease.
Aaide from Prof Anskar , the research’s first-authors include Dr Cheuk Him-man, Research Assistant Professor, and Eunis Lam and Dr Kenny Dang, MPhil and PhD students, respectively, Department of Medicine, School of Clinical Medicine, HKUMed; and major collaborators include Dr Carmen Wong Chak-lui, Associate Professor, Department of Pathology, School of Clinical Medicine, HKUMed; Professor Michael Huen Shing-yan, Professor, School of Biomedical Sciences, HKUMed; Professor Eric So, King’s College London, UK; and Professor Mak Tak-wah, Princess Margaret Cancer Centre, Toronto, Canada.
Research method and findings
A comprehensive analysis of gene expression and pharmacological vulnerabilities in different AML subtypes identified a gene known as polo-like kinase 4 (PLK4), which is specifically active in TP53 mutated AML. PLK4 is a major regulator of cell division. TP53 mutated AML is resistant to chemotherapy and highly vulnerable to prolonged PLK4 inhibition. PLK4 inhibition also induces DNA damage, cell ageing and abnormal cell division. The team discovered that the combined effects of histone modification and polyploidy activate the cGAS-STING pathway, which triggers the immune system. These findings have been consistently observed in both the laboratory setting and animal models. The combination of the PLK4 inhibitor with a monoclonal antibody against CD47 enhanced macrophage killing capability, synergistically reducing the leukemic burden and resulting in prolonged animal survival.
Significance of the study
This is the first study to demonstrate the therapeutic effect of PLK4 inhibition on TP53 mutated AML and the novel therapeutic mechanism pertaining to the activation of the cGAS-STING pathway and the immune system. These observations lay a foundation for evaluating the clinical effects of PLK4 inhibitor in patients with this AML subtype. In addition to hospitals in the US and Canada, the Haematology Division at Queen Mary Hospital will become a treatment site that is participating in global clinical trials to test the effects of PLK4 inhibitor in AML patients. (Press Release)
