Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia

Monique Dail, Jason Wong, Jessica Lawrence, Daniel O’Connor, Joy Nakitandwe, Shann-Ching Chen, Jin Xu, Leslie B. Lee, Keiko Akagi, Qing Li, Jon C. Aster, Warren S. Pear, James R. Downing, Deepak Sampath and Kevin Shannon ()
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Monique Dail: University of California
Jason Wong: University of California
Jessica Lawrence: University of California
Daniel O’Connor: University of California
Joy Nakitandwe: St Jude Children’s Research Hospital
Shann-Ching Chen: St Jude Children’s Research Hospital
Jin Xu: University of California
Leslie B. Lee: Genentech Inc.
Keiko Akagi: Immunology and Medical Genetics, Ohio State University
Qing Li: University of Michigan
Jon C. Aster: Brigham & Women’s Hospital, Harvard Medical School
Warren S. Pear: Perelman School of Medicine, University of Pennsylvania
James R. Downing: St Jude Children’s Research Hospital
Deepak Sampath: Genentech Inc.
Kevin Shannon: University of California

Nature, 2014, vol. 513, issue 7519, 512-516

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13495

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