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• W1973297092 abstract "Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and KrasG12D mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL. Mutations that dysregulate Notch1 and Ras/PI3K signalling are common in T-cell acute lymphoblastic leukaemia; here, treatment with a PI3K inhibitor is shown to induce drug resistance that is associated with downregulation of activated Notch1 signalling, suggesting that inhibition of both Notch1 and PI3K could promote drug resistance. T-cell acute lymphoblastic leukaemia (T-ALL) is closely associated with mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K) signalling. Kevin Shannon and colleagues show that treatment with GDC-0941 (pictilisib), a PI3K inhibitor that is advancing in clinical development, induces resistance associated with downregulation of activated Notch signalling, cross-resistance to γ-secretase inhibitors and upregulated PI3K signalling. Inhibition of Notch1 activates the PI3K pathway, suggesting that the rational strategy of concurrently targeting activated Notch1 and PI3K in T-ALL is likely to accelerate drug resistance." @default.
• W1973297092 created "2016-06-24" @default.
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• W1973297092 date "2014-07-20" @default.
• W1973297092 modified "2023-10-17" @default.
• W1973297092 title "Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia" @default.
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• W1973297092 doi "https://doi.org/10.1038/nature13495" @default.
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