Targeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies

Abstract

Sterile α motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTPs) triphosphohydrolase that can hydrolyze dNTPs into deoxynucleosides and triphosphates to keep the balance of the intracellular dNTPs pool. Moreover, it has been reported that SAMHD1 plays a role in regulating cell proliferation and the cell cycle, maintaining genome stability and inhibiting innate immune responses. SAMHD1 activity is regulated by phosphorylation, oxidation, SUMOylation, and O-GlcNAcylation. SAMHD1 mutations have been reported to cause diseases, including chronic lymphocytic leukemia and mantle cell lymphoma. SAMHD1 expression in acute myeloid leukemia predicts inferior prognosis. Recently, it has been revealed that SAMHD1 mediates the resistance to anti-cancer drugs. This review will focus on SAMHD1 function and regulation, the association between SAMHD1 and hematological malignancies and will provide updated information on SAMHD1 mediating resistance to nucleoside analogue antimetabolites, topoisomerase inhibitors, platinum-derived agents and DNA hypomethylating agents. Furthermore, histone deacetylase inhibitors and tyrosine kinase inhibitors indirectly increase anti-cancer drug resistance by increasing SAMDH1 activity. We herein highlight the importance of the development of novel agents targeting SAMHD1 to overcome treatment resistance of hematological malignancies, which would be an opportunity to improve the outcome of patients with refractory hematological malignancies.

Keywords: Anti-cancer drugs; Hematological malignancies; Regulation; Resistance mechanism; SAMHD1.

Figure 1

SAMHD1 hydrolyzes deoxynucleoside triphosphate (dNTPs), regulates the cell cycle, and inhibits innate immunity. SAMHD1 subunit forms tetramer mediates by GTP/dGTP binding to SAMHD1 guanine-specific allosteric sites (A1) and dNTPs binding to allosteric sites (A2). SAMHD1 tetramers are phosphorylated by the cyclinA2/CDK complex in S/G2 transition to inhibit SAMHD1 dNTPase activity and are dephosphorylated by protein phosphatase 2A (PP2A). SAMHD1 hydrolyzes dNTPs into deoxynucleoside and triphosphate to keep the intracellular balance of the dNTPs pool. SAMHD1 restricts retrovirus infections at reverse transcription stage by depleting intracellular dNTPs. SAMHD1 inhibits innate immunity by suppressing virus DNA replication in the cytoplasm and by keeping cytoplasm single-strand DNA at a low level insufficient to initiate cGAS-STING pathway to induce type Ι interferon secretion. SAMHD1 inhibits the TRAF6-TAK1axis to inhibit activation of the NF-κB signaling pathway. SAMHD1 binds the CtBP-interacting protein (CtIP) to mediate DNA double-strand break (DSB) end resection to initiate DNA homologous recombination repair. pSAMHD1, phosphorylated SAMHD1; TNF receptor-associated factor 6 (TRAF6); transforming growth factor β-activated kinase 1 (TAK1); IKK, inhibitor of kappa B kinase; cGAS, cyclic GMP-AMP synthase; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; STING, stimulator of interferon genes; IRF, interferon regulatory factor.

Figure 2

SAMHD1 mutations in CLL and MCL. SAMHD1 has 626 amino acid residues, including a sterile α motif domain SAM (45–110) and a histidine/aspartic acid (HD) domain (115–562). In the schematic diagram, mutations of CLL are marked in blue and mutations of MCL are marked in red. R451H in purple is reported in both CLL and MCL. Among these mutation sites, Arg145, Tyr155, Pro158, and Arg451 are the key residues of allosteric sites; His206 and Arg366 are in composition of the catalytic active center; and Cys355 is the cysteine for oxidation regulation. Other functions of mutation sites displayed have not yet been elucidated.

Figure 3

SAMHD1 mediates resistance of multiple anti-cancer drugs. Nucleoside analogues are prodrug forms and are phosphorylated to active forms by cellular kinases. SAMHD1 catalyzes the hydrolysis of phosphorylated nucleoside analogues into inactive prodrug forms and triphosphate. DNA hypomethylating agent (HMA), decitabine, is phosphorylated to decitabine-TP and inhibits DNA methyltransferase (DNMT). SAMHD1 hydrolyzes decitabine-TP to decitabine and triphosphate. Topoisomerase inhibitor, platinum-derived agents, and radiotherapy mediates DNA double-strand breaks (DSBs) in cancer cells and kill cancer cells. SAMHD1 binds CtBP-interacting protein (CtIP) and facilitates DSB end resection to initiate DNA homologous recombination and increase resistance to DNA damage agents. Histone deacetylase inhibitors (HDACi) up-regulate p53/p27phosphorylation. Phosphorylated p27 binds the cyclinA2/CDK complex to inhibit its function of mediating SAMHD1 phosphorylation. Tyrosine kinase inhibitors (TKIs) inhibit intracellular kinase to phosphorylate SAMHD1 and increase PP2A activity to dephosphorylated SAMHD1. HDACi and TKIs decrease phosphorylated SAMHD1 and indirectly increase SAMHD1 mediating the resistance of other agents. HAT, histoneacetyltransferase.