Article: Molecular Pathways: Targeting the PI3K Pathway in Cancer-BET Inhibitors to the Rescue.
Clinical cancer research : an official journal of the American Association for Cancer Research
2016 Volume 22, Issue 11, Page(s) 2605–2610
Abstract: The PI3K signaling pathway is a complex and tightly regulated network that is critical for many physiologic processes, such as cell growth, proliferation, metabolism, and survival. Aberrant activation of this pathway can occur through mutation of almost ... ...
| Abstract | The PI3K signaling pathway is a complex and tightly regulated network that is critical for many physiologic processes, such as cell growth, proliferation, metabolism, and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases, including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small-molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Recently, targeting proteins of the bromodomain and extraterminal (BET) family of epigenetic readers of histone acetylation has been shown to effectively block adaptive signaling response of cancer cells to inhibitors of the PI3K pathway, which at least in some cases can restore sensitivity. BET inhibitors also enforce blockade of the MAPK, JAK/STAT, and ER pathways, suggesting they may be a rational combinatorial partner for divergent oncogenic signals that are subject to homeostatic regulation. Here, we review the PI3K pathway as a target for cancer therapy and discuss the potential use of BET inhibition to enhance the clinical efficacy of PI3K inhibitors. Clin Cancer Res; 22(11); 2605-10. ©2016 AACR. |
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| MeSH term(s) | Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Synergism ; Epigenesis, Genetic/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proteins/antagonists & inhibitors ; Signal Transduction |
| Chemical Substances | Antineoplastic Agents ; Protein Kinase Inhibitors ; Proteins ; bromodomain and extra-terminal domain protein, human ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) |
| Language | English |
| Publishing date | 2016--01 |
| Publishing country | United States |
| Document type | Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1225457-5 |
| ISSN | 1557-3265 ; 1078-0432 |
| ISSN (online) | 1557-3265 |
| ISSN | 1078-0432 |
| DOI | 10.1158/1078-0432.CCR-15-2389 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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