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.
Highlights
T-cell acute lymphoblastic leukemia (T-Acute lymphoblastic leukemia (ALL)) is the most common form of malignancy in children and is classified by the abnormal accumulation of immature lymphoblasts of the T-cell lineage [1]
We found a number of hematological subtypes with IC50 values < 9 μM in greater than 50% of the cell lines profiled, including T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and non-Hodgkin lymphoma (NHL) (Figure 1G and Table 1)
Whilst we focussed on hematological malignancies and T-ALL, this phosphoinositide 3-kinase (PI3K) pharmacology dataset can be used as a resource for further interrogation and validation of PI3K pathway biology and sensitivity
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is the most common form of malignancy in children and is classified by the abnormal accumulation of immature lymphoblasts of the T-cell lineage [1]. Activating mutations in NOTCH1 are present in 55–60% of T-ALL and mutations in PTEN and the phosphoinositide 3-kinase (PI3K) pathway are present in 47% of pediatric cases [2,3,4,5]. The discovery of these recurring mutations has led to pre-clinical studies investigating the potential for using NOTCH and PTEN pathway agents in T-ALL. The PI3K/AKT/mTOR signaling pathway is the most frequently activated signaling network in cancer and recurring mutations in this network have been identified, including mutations (PIK3CA, AKT, and PTEN), amplifications (PIK3CA, PIK3CB and AKT)
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