Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity DOI Open Access
Sauveur-Michel Maira,

Frédéric Stauffer,

Josef Brueggen

et al.

Molecular Cancer Therapeutics, Journal Year: 2008, Volume and Issue: 7(7), P. 1851 - 1863

Published: July 1, 2008

Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft these enzymes. In cellular settings using cell lines, this molecule able effectively specifically block dysfunctional activation pathway, inducing G1 arrest. translates well vivo models cancer. Thus, compound was tolerated, displayed disease stasis when administered orally, enhanced efficacy other agents used combination studies. Ex pharmacokinetic/pharmacodynamic analyses tissues showed a time-dependent correlation between concentration PI3K/Akt inhibition. Collectively, preclinical data show potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. currently phase I clinical trials. [Mol Cancer Ther 2008;7(7):1–13 2008;7(7):1851–13]

Language: Английский

Hallmarks of Cancer: The Next Generation DOI Creative Commons
Douglas Hanahan, Robert A. Weinberg

Cell, Journal Year: 2011, Volume and Issue: 144(5), P. 646 - 674

Published: March 1, 2011

Language: Английский

Citations

59953
mTOR: from growth signal integration to cancer, diabetes and ageing DOI
Roberto Zoncu, Alejo Efeyan, David M. Sabatini

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2010, Volume and Issue: 12(1), P. 21 - 35

Published: Dec. 15, 2010

Language: Английский

Citations

3814
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism DOI
Jeffrey A. Engelman, Ji Luo, Lewis C. Cantley

et al.

Nature Reviews Genetics, Journal Year: 2006, Volume and Issue: 7(8), P. 606 - 619

Published: July 18, 2006

Language: Английский

Citations

3154
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB DOI Creative Commons
Dos D. Sarbassov, Siraj M. Ali,

Shomit Sengupta

et al.

Molecular Cell, Journal Year: 2006, Volume and Issue: 22(2), P. 159 - 168

Published: April 1, 2006

Language: Английский

Citations

2578
Targeting the phosphoinositide 3-kinase pathway in cancer DOI
Pixu Liu, Hailing Cheng, Thomas M. Roberts

et al.

Nature Reviews Drug Discovery, Journal Year: 2009, Volume and Issue: 8(8), P. 627 - 644

Published: July 31, 2009

Language: Английский

Citations

2552
Targeting PI3K signalling in cancer: opportunities, challenges and limitations DOI
Jeffrey A. Engelman

Nature reviews. Cancer, Journal Year: 2009, Volume and Issue: 9(8), P. 550 - 562

Published: July 24, 2009

Language: Английский

Citations

2322
The PI3K Pathway in Human Disease DOI Creative Commons
David A. Fruman, Honyin Chiu, Benjamin D. Hopkins

et al.

Cell, Journal Year: 2017, Volume and Issue: 170(4), P. 605 - 635

Published: Aug. 1, 2017

Language: Английский

Citations

2171
Insulin and insulin-like growth factor signalling in neoplasia DOI
Michaël Pollak

Nature reviews. Cancer, Journal Year: 2008, Volume and Issue: 8(12), P. 915 - 928

Published: Nov. 24, 2008

Language: Английский

Citations

1949
Ras, PI(3)K and mTOR signalling controls tumour cell growth DOI
Reuben J. Shaw, Lewis C. Cantley

Nature, Journal Year: 2006, Volume and Issue: 441(7092), P. 424 - 430

Published: May 1, 2006

Language: Английский

Citations

1944
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways DOI Open Access
Ping Wee, Zhixiang Wang

Cancers, Journal Year: 2017, Volume and Issue: 9(5), P. 52 - 52

Published: May 17, 2017

The epidermal growth factor receptor (EGFR) is a tyrosine kinase that commonly upregulated in cancers such as non-small-cell lung cancer, metastatic colorectal glioblastoma, head and neck pancreatic breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations truncations to its extracellular domain, EGFRvIII truncations, well L858R T790M mutations, or exon 19 truncation. These aberrations over-activate downstream pro-oncogenic signaling pathways, RAS-RAF-MEK-ERK MAPK AKT-PI3K-mTOR pathways. pathways then activate many biological outputs are beneficial cancer cell proliferation, their chronic initiation progression through cycle. Here, we review molecular regulate signal transduction, structure ligand binding dimerization, lead G1 cycle progression. We focus on induction CYCLIN D expression, CDK4/6 activation, repression cyclin-dependent inhibitor proteins (CDKi) by also discuss successes challenges EGFR-targeted therapies, potential for use combination with inhibitors.

Language: Английский

Citations

1589