Fig. 6
Acquired resistance to CNDAC is associated with decreased DCK levels and accompanied by cross-resistance to DCK-dependent nucleoside analogues. (A) Schematic illustrations of the establishment of CNDAC-resistant HL-60 and PL-21 cells by step-wise increasing drug concentrations during cell culture and of the establishment of single cellderived clones by limiting dilution. Moreover, representative Western blots indicating SAMHD1 and DCK levels in CNDAC-adapted HL-60 (HL-60rCNDACI-XII) and PL-21 (PL-21rCNDACI-XII) sublines and in single cell-derived clonal sublines of these cell lines. GAPDH and β-Actin served as loading controls. (B) Resistance profiles of CNDAC-adapted HL-60 and PL-21 sublines and single cell-derived clones of HL-60 and PL-21. Left spider webs show sensitivity to the cytotoxic drugs CNDAC, 6-Thioguanine (6-TG), Clofarabine (CLOF), Cladribine (CLAD), Fludarabine (FLU), Gemcitabine (GEM), Decitabine (DAC), 5-Azacytidine (AZA), Daunorubicin (DAU), Cytarabine (ARA-C), and Sapacitabine (SAP), while right spider webs display sensitivity to the targeted drugs Vismodegib (VISMO), Olaparib (OLA), Ganetespib (GANE), Gedatolisib (GEDA), Volasertib (VOLA), Molibresib (MOLI), and Venetoclax (VENE). Values are depicted as fold changes in drug concentrations that reduce cell viability by 50% (IC50s) between the respective parental AML cell line (shown in red) and the resistant cell lines or clones. Points closer to the centre than red lines indicate higher sensitivity to drugs in CNDAC-resistant sublines or clonal sublines than in parental cell lines, while points lying outside red lines indicate reduced sensitivity to the respective drug. IC50 fold changes are shown as means from three independent experiments. Numerical values are provided in Supplementary Table 6