title: Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen.
abstract: Selective phosphoinositide 3-kinase (PI3K)/AKT/mTOR inhibitors are currently under evaluation in clinical studies. To identify tumor types that are sensitive to PI3K pathway inhibitors we screened compounds targeting PI3Kα/δ (AZD8835), PI3Kβ/δ (AZD8186), AKT (AZD5363) and mTORC1/2 (AZD2014) against a cancer cell line panel (971 cell lines). There was an enrichment of hematological malignancies that were sensitive to AKT and mTOR inhibition, with the greatest degree of sensitivity observed in T-cell acute lymphoblastic leukemia (T-ALL). We found that all NOTCH mutant T-ALL cell lines were sensitive to AKT and mTORC1/2 inhibitors, with only partial sensitivity to agents that target the PI3K α, β or δ isoforms. Induction of apoptosis only occurred following AKTi treatment in cell lines with PTEN protein loss and high levels of active AKT. In summary, we have demonstrated that T-ALL cell lines show differential sensitivity to inhibition at different nodes in the PI3K/AKT/mTOR pathway and inhibiting AKT or mTOR may have a therapeutic benefit in this disease setting.
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: James T
authors.initials: JT
authors.lastname: Lynch
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: McEwen
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, United Kingdom.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, United Kingdom.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: AKT; Notch; PI3K; leukemia; mTOR