PNP inhibitors selectively kill cancer cells lacking SAMHD1

Tamara Davenne; Jan Rehwinkel

doi:10.1080/23723556.2020.1804308

PNP inhibitors selectively kill cancer cells lacking SAMHD1

Mol Cell Oncol. 2020 Sep 20;7(6):1804308. doi: 10.1080/23723556.2020.1804308.

Authors

Tamara Davenne^{1

2}, Jan Rehwinkel¹

Affiliations

¹ Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² InhaTarget Therapeutics, Gosselies, Belgium.

Abstract

Purine nucleoside phosphorylase inhibitors (PNP-Is) were developed to ablate transformed lymphocytes. However, only some patients with leukemia benefit from PNP-Is. We provide a molecular explanation: the deoxyribonucleoside triphosphate (dNTP) hydrolase SAM and HD domain-containing protein 1 (SAMHD1) prevents the accumulation of toxic dNTP levels during purine nucleoside phosphorylase inhibition. We propose PNP-Is for targeted therapy of patients with acquired SAMHD1 mutations.

Keywords: CLL; PNP; SAMHD1; forodesine; leukemia.

Abstract

Grants and funding