Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Processing Request
Upregulation of Receptor Tyrosine Kinase Activity and Stemness as Resistance Mechanisms to Akt Inhibitors in Breast Cancer.
Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Processing Request
- المؤلفون: Tsang, Tiffany; He, Qingling; Cohen, Emily B.; Stottrup, Casey; Lien, Evan C.; Zhang, Huiqi; Lau, C. Geoffrey; Chin, Y. Rebecca
- المصدر:
Cancers; Oct2022, Vol. 14 Issue 20, p5006-N.PAG, 17p
- الموضوع:
- معلومة اضافية
- الموضوع:
- نبذة مختصرة :
Simple Summary: Acquired resistance of cancer cells to targeted therapy poses a major clinical problem. Hyperactivation of the PI3K/Akt pathway is common in human malignancies, and numerous Akt inhibitors are undergoing clinical evaluation. However, mechanisms of acquired resistance to Akt inhibitors have not been studied extensively. By using phospho-RTK arrays, we demonstrated hyper-phosphorylation of multiple RTKs in Akt-inhibitor-resistant breast cancer cells. We further showed that the EGFR inhibitor could overcome Akt inhibitor resistance. In addition, our study revealed enhanced cancer stemness in resistant cells, and RNA sequencing identified several stem cell regulators that may contribute to acquired resistance. The PI3K/Akt pathway is frequently deregulated in human cancers, and multiple Akt inhibitors are currently under clinical evaluation. Based on the experience from other molecular targeted therapies, however, it is likely that acquired resistance will be developed in patients treated with Akt inhibitors. We established breast cancer models of acquired resistance by prolonged treatment of cells with allosteric or ATP-competitive Akt inhibitors. Phospho-Receptor tyrosine kinase (Phospho-RTK) arrays revealed hyper-phosphorylation of multiple RTKS, including EGFR, Her2, HFGR, EhpB3 and ROR1, in Akt-inhibitor-resistant cells. Importantly, resistance can be overcome by treatment with an EGFR inhibitor. We further showed that cancer stem cells (CSCs) are enriched in breast tumor cells that have developed resistance to Akt inhibitors. Several candidates of CSC regulators, such as ID4, are identified by RNA sequencing. Cosmic analysis indicated that sensitivity of tumor cells to Akt inhibitors can be predicted by ID4 and stem cell/epithelial–mesenchymal transition pathway targets. These findings indicate the potential of targeting the EGFR pathway and CSC program to circumvent Akt inhibitor resistance in breast cancer. [ABSTRACT FROM AUTHOR]
- نبذة مختصرة :
Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
No Comments.