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Selective Inactivation of Cancer Drugs by SAMHD1 Provides a Molecular Rationale for Therapeutic Stratification in AML

: Schneider, C.; Oellerich, T.; Knecht, K.M.; Thomas, D.; Buzovetsky, O.; Schliemann, C.; Bohnenberger, H.; Angenendt, L.; Hartmann, W.; Wardelmann, E.; Scheich, S.; Comoglio, F.; Wilke, A.; Ströbel, P.; Serve, H.; Geisslinger, G.; Keppler, O.T.; Xiong, Y.; Cinatl, J.

Annals of Hematology 98 (2019), Supplement 1, pp.S28-S29
ISSN: 0939-5555
ISSN: 0945-8077
ISSN: 1432-0584
International Symposium "ACUTE LEUKEMIAS" <17, 2019, Munich>
Fraunhofer IME ()

Background: Nucleoside analog (NA) drugs are widely used to treat a variety of cancers, including acute myeloid leukemia (AML). With an essential role in regulating the cellular dNTP pool by degrading cellular nucleotides, SAMHD1 has the potential to decrease the cellular concentration of frequently prescribed NAs and thereby diminish their clinical efficacy in cancer therapy.
Method: In this study, we used biochemical, structural, and cell based methods to examine the interaction of SAMHD1 with various AML cancer drugs, including cytarabine, cladribine, clofarabine, fludarabine, gemcitabine and the two DNA-hypomethylating agents (HMAs) decitabine and azacytidine.
Results: We found that both the catalytic and the allosteric sites of SAMHD1 can bind NAs and that the SAMHD1 substrate specificity is regulated by 2′ sugar modifications of the nucleotide analogs. Cell culture, AML blasts and xenotransplantation models confirmed the crystallography findings that most of these drugs are affected by SAMHD1 activity, while some stay unaffected. In accordance with these data expression levels of SAMHD1 are correlating with survival parameters in patients treated with SAMHD1-dependent NAs.
Conclusion: Taken together, these results establish SAMHD1 as a substrate-specific resistance factor that has promise as a predictive biomarker for drug stratification and a therapeutic target in nucleoside analog-based AML therapy. Conflict of interest: none