Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen
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James T. Lynch1, Robert McEwen1, Claire Crafter1, Ultan McDermott2, Mathew J. Garnett2, Simon T. Barry1, Barry R. Davies1
1Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom
2Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, United Kingdom
James T. Lynch, e-mail: [email protected]
Keywords: PI3K, AKT, mTOR, Notch, leukemia
Received: November 16, 2015 Accepted: February 18, 2016 Published: March 10, 2016
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.
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