Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment.

Oncotarget
Alberto M MartelliJames A McCubrey

Abstract

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are two key components of the PI3K/Akt/mTOR signaling pathway. This signal transduction cascade regulates a wide range of physiological cell processes, that include differentiation, proliferation, apoptosis, autophagy, metabolism, motility, and exocytosis. However, constitutively active PI3K/Akt/mTOR signaling characterizes many types of tumors where it negatively influences response to therapeutic treatments. Hence, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors may improve cancer patient outcome. The PI3K/Akt/mTOR signaling cascade is overactive in acute leukemias, where it correlates with enhanced drug-resistance and poor prognosis. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds targeting the catalytic site of both kinases. In preclinical models, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against acute leukemia cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin. At variance with rapamycin, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited th...Continue Reading

References

Apr 1, 1996·The Journal of Experimental Medicine·M A GoodellR C Mulligan
Sep 30, 1999·The New England Journal of Medicine·B LöwenbergA Burnett
Jan 27, 2000·Cell·D Hanahan, R A Weinberg
Jun 1, 2002·Science·Lewis C Cantley
Nov 7, 2002·Cell·Derek P BrazilBrian A Hemmings
Dec 6, 2003·Proceedings of the National Academy of Sciences of the United States of America·Valerie I BrownStephan A Grupp
Apr 7, 2004·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Noriko OshiroKazuyoshi Yonezawa
May 8, 2004·Trends in Biochemical Sciences·Derek P BrazilBrian A Hemmings
Jul 9, 2004·Biochemical and Biophysical Research Communications·Shahab UddinKishor G Bhatia
Aug 7, 2004·The Hematology Journal : the Official Journal of the European Haematology Association·Motohiro WakabayashiMasakazu Nitta
Aug 19, 2004·Journal of Cellular Physiology·Giovanna TabelliniAlberto M Martelli
Aug 26, 2004·British Journal of Haematology·Pier Luigi TazzariAlberto M Martelli
Oct 7, 2004·Nature Cell Biology·Estela JacintoMichael N Hall
Nov 20, 2004·Blood·Christian RécherBernard Payrastre
Mar 22, 2005·The International Journal of Biochemistry & Cell Biology·Ana MarkovicRichard B Lock
Mar 23, 2005·Cancer Research·Michael G Kharas, David A Fruman
May 10, 2005·Blood·Raffaella AvellinoMaria Fiammetta Romano

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Citations

Nov 5, 2013·Oncotarget·Maria Giovanna Francipane, Eric Lagasse
Jun 17, 2014·Oncotarget·James A McCubreyMelchiorre Cervello
May 20, 2015·International Journal of Molecular Sciences·Calvin R JustusLi V Yang
Oct 16, 2015·Cellular Oncology (Dordrecht)·Jessika BertacchiniNajmaldin Saki
May 26, 2015·Expert Review of Anticancer Therapy·Xavier Thomas
Sep 22, 2015·Autophagy·Harun-Or RashidHan-Jung Chae
Feb 1, 2017·Molecular Cancer·Kodappully Sivaraman SiveenRamzi M Mohammad
Mar 11, 2018·Clinical Science·Alberto M MartelliJames A McCubrey
Feb 9, 2020·International Journal of Molecular Sciences·Chiara TarantelliFrancesco Bertoni
Aug 13, 2013·Aging·Mikhail V Blagosklonny
Feb 26, 2015·Cellular and Molecular Life Sciences : CMLS·Jessika BertacchiniNajmaldin Saki
Jun 13, 2013·Expert Opinion on Therapeutic Targets·Camilla EvangelistiAlberto M Martelli
Mar 5, 2013·Oncotarget·James A McCubreyZoya N Demidenko
Jun 28, 2014·International Journal of Oncology·Camilla EvangelistiAlberto M Martelli
Nov 17, 2015·Cell Death Discovery·Alexander S WatsonAnna Katharina Simon
May 7, 2020·Journal of Biomedical Science·Jing ZhangBee Luan Khoo
Feb 28, 2014·Oncoimmunology·Mikhail V Blagosklonny
Mar 26, 2013·Acta Pharmacologica Sinica·Ya-ping YangChun-feng Liu
Jul 1, 2015·Neurosurgery·Patrick J CiminoSonika Dahiya
May 23, 2015·Circulation Research·Patrick M McLendon, Jeffrey Robbins
Dec 6, 2014·Cell Death & Disease·M V Blagosklonny
Feb 24, 2019·Cells·Carolina SimioniLuca M Neri
Apr 15, 2015·Oncotarget·Sabina HonischFlorian Lang

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Methods Mentioned

BETA
xenograft
flow cytometry

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