Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling.

PloS One
Qing-Bai SheNeal Rosen

Abstract

Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy. A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the la...Continue Reading

References

Oct 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·J Q ChengJ R Testa
Jul 25, 1998·The Biochemical Journal·N J HellyerJ G Koland
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·X WuC L Sawyers
Feb 1, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Charles L VogelMichael Press
Mar 28, 2002·Diabetes·Madeline ButlerBrett P Monia
Jun 1, 2002·Science·Lewis C Cantley
Jul 3, 2002·Nature Reviews. Cancer·Igor Vivanco, Charles L Sawyers
Jul 6, 2002·Science·I Bernard Weinstein
Jun 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Pradip K MajumderWilliam R Sellers
Jul 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·Thomas HolbroNancy E Hynes
Feb 6, 2004·Breast Cancer Research and Treatment·Marc Lacroix, Guy Leclercq
Mar 16, 2004·Science·Yardena SamuelsVictor E Velculescu
Apr 10, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David FinkleSharon Erickson
Jul 16, 2004·Cancer Biology & Therapy·Kurtis E BachmanBen Ho Park
Aug 3, 2004·Genes, Chromosomes & Cancer·Jose M GarcíaFelix Bonilla
May 3, 2005·Nature Reviews. Cancer·Nancy E Hynes, Heidi A Lane
Jun 30, 2005·Cancer Metastasis Reviews·Gavin P Robertson
Feb 3, 2006·Cancer Research·Kathryn E O'ReillyNeal Rosen
Jan 16, 2007·Cell·Xinjiang WangXuejun Jiang
Apr 25, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lao H SaalRamon Parsons
Jul 3, 2007·Cell·Brendan D Manning, Lewis C Cantley
Aug 2, 2007·Anti-cancer Drugs·Jaclyn LoPiccoloPhillip A Dennis
Dec 15, 2007·Genes & Development·Sreenath V Sharma, Jeffrey Settleman
Jan 24, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Stephen JohnstonNeil L Spector
May 16, 2008·Bioorganic & Medicinal Chemistry Letters·Mark T BilodeauGeorge D Hartman

❮ Previous
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Citations

Apr 1, 2009·Future Medicinal Chemistry·Sauveur-Michel MairaFrédéric Stauffer
Sep 6, 2014·Breast Cancer Research : BCR·Dimitrios ZardavasSherene Loi
Mar 25, 2014·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·V VinodSrinivas Gopala
Sep 6, 2014·Cancer Chemotherapy and Pharmacology·Robert G LingemanLinda H Malkas
Dec 18, 2013·Women's Health·Jonathan D BlackAlessandro D Santin
Oct 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Anthony C FaberJeffrey A Engelman
Dec 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Saskia M BrachmannSauveur-Michel Maira
Jan 21, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kevin D CourtneyJeffrey A Engelman
Sep 10, 2010·Science Translational Medicine·Andrea P Myers, Lewis C Cantley
Jul 16, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ipsita Dey-GuhaSridhar Ramaswamy
Oct 14, 2011·The New England Journal of Medicine·Dennis SlamonUNKNOWN Breast Cancer International Research Group
Oct 20, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Todd W MillerCarlos L Arteaga
Feb 10, 2012·Breast Cancer Research : BCR·Todd W Miller
Feb 14, 2012·Cancer Discovery·Aphrothiti J HanrahanDavid B Solit
May 24, 2012·Neuro-oncology·Patrick Y WenW K Alfred Yung
Aug 2, 2013·Science Translational Medicine·Moshe ElkabetsJosé Baselga
Mar 28, 2013·Science Signaling·Anne RoulstonGordon C Shore
Mar 28, 2013·Science Signaling·Gregory R BeanEmily H-Y Cheng
Oct 6, 2010·Cancer Metastasis Reviews·Carlos A CastanedaEva M Ciruelos

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Methods Mentioned

BETA
flow cytometry
xenografts
xenograft
transgenic
Assay

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