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Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a
James T Lynch1, Robert McEwen1, Claire Crafter1
1Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
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.
Insights
Targeting the PI3K/AKT/mTOR pathway with inhibitors shows promise, particularly for T-cell acute lymphoblastic leukemia (T-ALL). AKT and mTOR inhibition demonstrated significant sensitivity in T-ALL cell lines, suggesting potential therapeutic benefits.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is crucial in cancer cell proliferation and survival.
- Selective inhibitors targeting different nodes of this pathway are under clinical investigation for various cancers.
Purpose of the Study:
- To identify tumor types sensitive to PI3K pathway inhibitors.
- To evaluate the efficacy of specific PI3K/AKT/mTOR inhibitors in a large cancer cell line panel.
Main Methods:
- Screening of 971 cancer cell lines against PI3Kα/δ, PI3Kβ/δ, AKT, and mTORC1/2 inhibitors.
- Analysis of sensitivity patterns across different cancer types and genetic mutations, including NOTCH and PTEN status.
Main Results:
- Hematological malignancies, especially T-cell acute lymphoblastic leukemia (T-ALL), showed enrichment for sensitivity to AKT and mTOR inhibition.
- All NOTCH-mutant T-ALL cell lines were sensitive to AKT and mTORC1/2 inhibitors.
- Apoptosis induction by AKT inhibitors was observed in cell lines with PTEN loss and high active AKT levels.
Conclusions:
- T-ALL cell lines exhibit differential sensitivity to PI3K/AKT/mTOR pathway inhibition at various molecular targets.
- Inhibition of AKT or mTOR may offer a therapeutic strategy for T-ALL.
