Fig. 5: Glucose limitation reveals a synthetic lethality to glutamine targeting in PI3K-driven leukemia.
From: A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer
A Relative cell viability of wild-type PI3K (n = 14 individual PDX) and PI3K-altered (n = 8 individual PDX) PDX blasts after 72 h of culture in complete or glucose-free medium with control (DMSO) or CB-839 1 µM treatment (mean + SEM are indicated). One-way ANOVA tests adjusted for multiple comparisons (Šidák correction) were run (*, p < 0.05; **, p < 0.01; ***, p < 0.001). B Relative cell viability of PI3K-altered (n = 8 individual PDX) PDX blasts after 72 h of culture in complete or glutamine-free medium with control (DMSO) or temsirolimus 200 nM treatment (mean + SEM are indicated). A one-way ANOVA test adjusted for multiple comparisons (Dunn–Šidák correction) was run (ns, p < 0.05; ***, p < 0.001). C Relative cell viability of wild-type PI3K (n = 14 individual PDX) and PI3K-altered (n = 8 individual PDX) PDX blasts after 72 h of culture treated with control (DMSO), CB-839 1 µM, temsirolimus 200 nM or combined treatment (mean + SEM are indicated, each dot is a biological replicate). A one-way ANOVA test adjusted for multiple comparisons (Dunnett correction) was run (***, p < 0.001). D Left: Heatmap depicting the Bliss synergy score of the combination CB-839 + temsirolimus computed from viability data of PI3K-altered PDX blasts (n = 7 individual PDX). Right: individual Bliss scores mapped to matched CB-839 IC50 values. A Bliss score >10 indicates synergy. E Relative cell viability of wild-type PI3K (n = 4 individual PDX) and PI3K-altered (n = 8 individual PDX) PDX blasts after 72 h of culture treated with control (DMSO), temsirolimus 200 nM, erwinase 1 U/ml or combined treatment (mean + SEM are indicated). A Kruskal-Wallis test adjusted for muliple comparisons (Dunn correction) was run (***, p < 0.001). F Relative cell viability of wild-type PI3K (n = 4 individual PDX) and PI3K-altered (n = 4 individual PDX) after 72 h of culture treated with control (DMSO), temsirolimus 200 nM, kidrolase 1 U/ml or combined treatment (mean + SEM are indicated). A Kruskal-Wallis test adjusted for multiple comparisons (Dunn correction) was run. G Survival curves of mice xenografted with two PI3K-altered PDX (5 mice/arm/PDX) and treated with vehicule, erwinase, CB-839, temsirolimus, or the indicated combinations. Outcome comparisons were performed using a Cox regression analysis (**, p < 0.01; ***, p < 0.001).
