Resistant Cancer Cell Line (RCCL) collection enables discovery of biomarker and drug target for the treatment of leukaemia patients
Acute myeloid leukaemia (AML) patients are treated with cytarabine-based chemotherapies. However, only a fraction of patients responds to chemotherapy. Non-responsive patients suffer from toxic side effects without experiencing therapeutic benefits. Therefore, biomarkers that reliably predict AML response to therapy are subject of intense research.
Recently, the Resistant Cancer Cell Line (RCCL) collection that is run by Prof. Martin Michaelis together with Prof Jindrich Cinatl (Goethe-University, Frankfurt am Main, Germany) enabled the discovery of a novel biomarker that identifies AML patients who will benefit from cytarabine-based chemotherapy with high accuracy.
Cytarabine becomes intracellularly activated by phosphorylation. Using cytarabine-adapted AML cell lines from the RCCL collection, the team that included Prof Michaelis and was led by Prof Cinatl discovered that the enzyme SAMHD1 removes the phosphate residues from the active form of cytarabine and reverses it into its inactive state. In accordance, the cellular SAMHD1 levels enabled the prediction of AML cell sensitivity to cytarabine. Further research showed that SAMHD1 levels determined in leukaemia cells also enabled the prediction of the clinical response in AML patients to cytarabine-based chemotherapies with high accuracy. Hence, SAMHD1 is a novel clinical biomarker that indicates which AML patients are likely to respond to cytarabin-based chemotherapies and which should not be treated by this regimen. In addition, inhibition of SAMHD1 effectively sensitises cytarabine-resistant AML cells to cytarabine-based chemotherapies, representing a novel therapeutic target in patients for whom currently no effective treatment exists.
The research was published in the journal Nature Medicine on 19th December 2016.