a23cf17b0fe96bac10ca10004ba36c43 pmc_32197329.pdf 638b8267931f8bc32549670c253c56927c9fd118 pmc_32197329.pdf 0260f97149d4b55dd79d79a196ecee838c9785db51ddb8d61ddfd61dcc5f786e pmc_32197329.pdf Title: Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy Subject: Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase involved in the regulation of the intracellular dNTP pool, linked to viral restriction, cancer development and autoimmune disorders. SAMHD1 function is regulated by phosphorylation through a mechanism controlled by cyclin-dependent kinases and tightly linked to cell cycle progression. Recently, SAMHD1 has been shown to decrease the efficacy of nucleotide analogs used as chemotherapeutic drugs. Here, we demonstrate that SAMHD1 can enhance or decrease the efficacy of various classes of anticancer drug, including nucleotide analogues, but also anti-folate drugs and CDK inhibitors. Importantly, we show that selective CDK4/6 inhibitors are pharmacological activators of SAMHD1 that act by inhibiting its inactivation by phosphorylation. Combinations of a CDK4/6 inhibitor with nucleoside or folate antimetabolites potently enhanced drug efficacy, resulting in highly synergic drug combinations (CI < 0.04). Mechanistic analyses reveal that cell cycle-controlled modulation of SAMHD1 function is the central process explaining changes in anticancer drug efficacy, therefore providing functional proof of the potential of CDK4/6 inhibitors as a new class of adjuvants to boost chemotherapeutic regimens. The evaluation of SAMHD1 expression in cancer tissues allowed for the identification of cancer types that would benefit from the pharmacological modulation of SAMHD1 function. In conclusion, these results indicate that the modulation of SAMHD1 function may represent a promising strategy for the improvement of current antimetabolite-based treatments. Keywords: SAMHD1; antimetabolite; CDK4/6; pemetrexed; HIV; cancer Author: Marc Castellví, Eudald Felip, Ifeanyi Jude Ezeonwumelu, Roger Badia, Edurne Garcia-Vidal, Maria Pujantell, Lucía Gutiérrez-Chamorro, Iris Teruel, Anna Martínez-Cardús, Bonaventura Clotet, Eva Riveira-Muñoz, Mireia Margelí and Ester Ballana Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Wed Mar 18 09:10:44 2020 CET ModDate: Wed Mar 18 09:10:44 2020 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2730497 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IWROEO+URWPalladioL-Ital Type 1 Custom yes yes no 116 0 RSJNYH+URWPalladioL-Bold Type 1 Custom yes yes no 117 0 IMCIKN+Rpxb Type 1 Builtin yes yes no 118 0 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