Publication Date:
2014-07-22
Description:
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 gamma-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dail, Monique -- Wong, Jason -- Lawrence, Jessica -- O'Connor, Daniel -- Nakitandwe, Joy -- Chen, Shann-Ching -- Xu, Jin -- Lee, Leslie B -- Akagi, Keiko -- Li, Qing -- Aster, Jon C -- Pear, Warren S -- Downing, James R -- Sampath, Deepak -- Shannon, Kevin -- K08 CA134649/CA/NCI NIH HHS/ -- K99 CA157950/CA/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA180037/CA/NCI NIH HHS/ -- R37 CA072614/CA/NCI NIH HHS/ -- R37 CA72614/CA/NCI NIH HHS/ -- U01 CA084221/CA/NCI NIH HHS/ -- England -- Nature. 2014 Sep 25;513(7519):512-6. doi: 10.1038/nature13495. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA. ; Division of Haematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, Brigham &Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043004" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Benzamides/pharmacology/therapeutic use
;
Clone Cells/drug effects/metabolism/pathology
;
Diphenylamine/analogs & derivatives/pharmacology/therapeutic use
;
Down-Regulation/drug effects
;
*Drug Resistance, Neoplasm/drug effects/genetics
;
Drug Synergism
;
Genes, ras/genetics
;
Indazoles/*pharmacology/therapeutic use
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
;
Phosphatidylinositol 3-Kinases/*antagonists & inhibitors
;
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug
;
therapy/*genetics/metabolism/pathology
;
Protein Kinase Inhibitors/*pharmacology/therapeutic use
;
Protein Structure, Tertiary
;
Proto-Oncogene Proteins c-akt/metabolism
;
Receptor, Notch1/chemistry/deficiency/genetics/*metabolism
;
Signal Transduction/drug effects
;
Sulfonamides/*pharmacology/therapeutic use
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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