Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML

Abstract

Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.

Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs (Review)

“…Conversely, the promoter of SAMHD1 has been demonstrated to be in an unmethylated state in THP-1 cells (23) and SAMHD1 protein expression does not increase following treatment with 5-AzadC. Furthermore, decitabine, which is a DNA methyltransferase inhibitor, has been demonstrated to be a substrate of SAMHD1, and its anticancer effect in acute myelocytic leukemia (AML) was found to be dependent of SAMHD1 protein expression (26). For other tumors characterized by methylation of the SAMHD1 promoter, further investigation is required to determine whether SAMHD1 could have a two-sided effect on chemotherapy with decitabine.…”

“…In 143 patients with AML who received ara-C-based chemotherapy, patients with low SAMHD1 expression levels had higher event-free survival rates than those with high SAMHD1 expression levels (37 vs. 19%, respectively), as well as higher 5-year overall survival rates (54 vs. 9%, respectively) (62). Furthermore, AML cells resistant to decitabine exhibit increased SAMHD1 protein expression, which could be a result of SAMHD1 promoter demethylation (26). In addition, SAMHD1 may also be considered as a useful biomarker for predicting the response to decitabine.…”

PNP inhibitors selectively kill cancer cells lacking SAMHD1

“…6,7 Subsequent work showed that SAMHD1 also protects cancer cells against other nucleoside-based compounds, including the DNA hypomethylating agent decitabine. 8,9 These observations and our work highlight the potential utility of SAMHD1 inhibitors, which we predict to sensitize SAMHD1-sufficient cancer cells to PNP-Is, cytarabine and other compounds. Interestingly, efforts to find a SAMHD1 inhibitor led to the discovery that ribonucleotide reductase (RNR) inhibitors sensitize cells to cytarabine.…”

“… 6 , 7 Subsequent work showed that SAMHD1 also protects cancer cells against other nucleoside-based compounds, including the DNA hypomethylating agent decitabine. 8 , 9 …”

SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP

“…As such, forodesine may have an advantage over other CLL drugs that inhibit B cell receptor signalling and thus target only “active” cells. In an independent line of investigations, SAMHD1 was found to not only degrade naturally occurring dNTPs but also some nucleotide analogues, including cytarabine (ara-C) and decitabine (DAC) that are used for treatment of acute myeloid leukaemia (AML) (Herold et al, 2017a; Herold et al, 2017b; Hollenbaugh et al, 2017; Oellerich et al, 2019; Schneider et al, 2017). The response of patients with AML to ara-C or DAC inversely correlates with SAMHD1 expression levels (Herold et al, 2017a; Oellerich et al, 2019; Schneider et al, 2017).…”