title: Efficacy of dual PI-3K and mTOR inhibitors in vitro and in vivo in acute lymphoblastic leukemia.
abstract: 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 Ser(473) and Thr(308) 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.
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia.
authors.forename: Jacky
authors.initials: J
authors.lastname: Wong
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Welschinger
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Hewson
authors.affiliation: Department of Haematology, Westmead Hospital, Westmead. NSW. Australia.
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000068338:Everolimus; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D057285:Precision Medicine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D000068338:Everolimus; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D020123:Sirolimus