Extended Data Fig. 9: Analysis of engraftment, tolerability, and efficacy of Selinexor combined with AKT inhibition in mouse models of AML.
a) Confirmation of PDX engraftment by measurement of circulating human CD45 + cells transplanted into NOG–EXL mice (n = 6 biologically independent mice per group); data are presented as mean + /- s.d. b) Bliss synergy analysis 2D plots for PDX model of AML treated with a dilution series of selinexor and ipatasertib. Delta scores indicate synergy (red) and antagonism (green) across drug-dilution matrix. c) Weight of C57BL/6 mice treated with vehicle or selinexor (15 mg/kg) plus ipatasertib (65 mg/kg). d) Weight of C57BL/6 mice treated with vehicle or chemotherapy (doxorubicin 1 mg/kg, cytarabine 100 mg/kg). e) Weight of C57BL/6 mice treated with vehicle or selinexor (15 mg/kg) plus chemotherapy (doxorubicin 1 mg/kg, cytarabine 100 mg/kg). f) Weight of C57BL/6 mice treated with vehicle or selinexor (7.5 mg/kg) plus chemotherapy (doxorubicin 1 mg/kg, cytarabine 100 mg/kg). g) Measurement by flow cytometry of the proportion of DsRed+ MLL-AF9 cells taken from bone marrows (n = 5 biologically independent mice per group) two days following treatment with vehicle, 15 mg/kg selinexor plus 65 mg/kg ipatasertib, chemotherapy (1 mg/kg doxorubicin and 100 mg/kg cytarabine), or 7.5 mg/kg selinexor plus chemotherapy; P values calculated using unpaired Mann-Whitney test; data are presented as mean + /- s.d. h) Measurement by flow cytometry of DsRed+ MLL-AF9 cells taken from bone marrows at the point of relapse observed in chemotherapy-treated mice (n = 5 biologically independent mice per group except in the chemotherapy-treated subgroup in which n = 4). P values calculated using unpaired Mann-Whitney test; data are presented as mean + /- s.d. i) Selinexor dose–response in OCI-AML2 and MOLM-13 cells treated with cytarabine (50 nM) or daunorubicin (5 nM) in the background; data are presented as mean + /- s.e.m. for n = 3 biologically independent experiments. Extended Data Fig. 9c-f Dosing schedule shown at bottom left. (D) = mouse demise.
