Research Papers:

Efficacy of dual PI-3K and mTOR inhibitors in vitro and in vivo in acute lymphoblastic leukemia

Jacky Wong _, Robert Welschinger, John Hewson, Kenneth . F Bradstock and Linda J. Bendall

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Oncotarget. 2014; 5:10460-10472. https://doi.org/10.18632/oncotarget.2260

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Jacky Wong1, Robert Welschinger1, John Hewson1, Kenneth F. Bradstock2 and Linda J. Bendall1

1 Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia

2 Department of Haematology, Westmead Hospital, Westmead. NSW. Australia


Linda Bendall, email:

Keywords: Acute lymphoblastic leukemia, Cell Signaling, Animal Models, PI-3K, mTOR

Received: April 08, 2014 Accepted: July 25, 2014 Published: July 25, 2014


The major regulators of human acute lymphoblastic leukemia (ALL) cell growth and survival mediate their effects through the phosphoinositide 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. We have shown that the mTOR inhibitor everolimus extended survival in a non-obese diabetic/severe combined immune-deficient (NOD/SCID) mouse xenograft model of human ALL. Since PI-3K has mTOR dependent and independent functions we examined the effect of the dual PI-3K/mTOR inhibitors BEZ235 and BGT226. These agents inhibited the proliferation of ALL cell lines with a three log greater potency than everolimus. However, the induction of cell death differed, with BGT226 being cytotoxic in the low micromolar range while a two log higher concentration of BEZ235 was required to produce the same effect. While all three agents extended the survival of NOD/SCID mice engrafted with human ALL, the responses of individual xenografts varied. Although differential phosphorylation of AKT on Ser473 and Thr308 in response to everolimus exposure was observed, this did not entirely explain the different in vivo responses to the drugs. Our data suggests that while dual PI-3K/mTOR inhibitors may improve therapeutic outcomes for a subset of ALL patients, patient selection will be important, with some patients likely to respond better to single mTOR inhibition.

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