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 Kras(G12D) 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / pharmacology
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Benzamides / therapeutic use
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Clone Cells / drug effects
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Clone Cells / metabolism
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Clone Cells / pathology
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Diphenylamine / therapeutic use
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Down-Regulation / drug effects
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Drug Resistance, Neoplasm* / drug effects
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Drug Resistance, Neoplasm* / genetics
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Drug Synergism
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Genes, ras / genetics
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Indazoles / pharmacology*
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Indazoles / therapeutic use
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Male
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Phosphoinositide-3 Kinase Inhibitors*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, Notch1 / chemistry
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Receptor, Notch1 / deficiency
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction / drug effects
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
Substances
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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Benzamides
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Indazoles
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Receptor, Notch1
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Sulfonamides
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mirdametinib
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Diphenylamine
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases