In vivo efficacy of PI3K pathway inhibition in Ph-like ALL. PDX models were treated with vehicle, PI3Kα inhibitor BYL719, PI3Kδ inhibitor idelalisib, PI3K/mTOR inhibitor gedatolisib, or TORC1/TORC2 inhibitor AZD2014 (n = 5 mice/treatment arm) daily for 2 to 4 weeks depending on rapidity of leukemia progression in vehicle-treated control animals. PI3K isoform or TORC1/TORC2 inhibition resulted in significant suppression of leukemia proliferation in peripheral blood and end-of-study spleens of most PDX models of (A) CRLF2-rearranged, (B) JAK1-mutant, (C) JAK2 fusion, and (D) ABL/PDGFR-mutant ALL vs vehicle controls. Gedatolisib most effectively inhibited ALL proliferation with near eradication of leukemia in CRLF2/JAK-mutant models and marked suppression in ABL/PDGFR-mutant models. Treatment groups were compared with the vehicle control for each PDX model via 1-way ANOVA with the Dunnett posttest for multiple comparisons with α = 0.05. *P < .05, **P < .01, ***P < .001, ****P < .0001.