title: Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia.
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.
authors.affiliation: Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Dail
authors.affiliation: Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Wong
authors.affiliation: Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lawrence
authors.affiliation: Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Connor
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Nakitandwe
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.affiliation: Division of Haematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pathology, Brigham &Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D011905:Genes, ras / Q000235:genetics; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D001549:Benzamides; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051881:Receptor, Notch1; D013449:Sulfonamides; C506614:mirdametinib; D004159:Diphenylamine; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases