Upregulation of Receptor Tyrosine Kinase Activity and Stemness as Resistance Mechanisms to Akt Inhibitors in Breast Cancer

Tiffany Tsang, Qingling He, Emily B. Cohen, Casey Stottrup, Evan C. Lien, Huiqi Zhang, C. Geoffrey Lau*, Y. Rebecca Chin*

*Corresponding author for this work

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

4 Citations (Scopus)
48 Downloads (CityUHK Scholars)

Abstract

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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Original languageEnglish
Article number5006
JournalCancers
Volume14
Issue number20
Online published13 Oct 2022
DOIs
Publication statusPublished - Oct 2022

Funding

This study was supported by the General Research Fund (11101517 to Y.R.C, 11104320 and 11104521 to C.G.L.) from the Research Grants Council (RGC) of the Hong Kong Special Administrative Region, the National Natural Science Foundation of China (81972781 to Y.R.C.), NIH National Cancer Institute (R00CA157945 to Y.R.C), V Foundation for Cancer Research (Y.R.C.), Research Impact Fund from RGC (R1020-18 to Y.R.C.) and Tung Foundation (9609302 to Y.R.C.).

Research Keywords

  • Akt
  • breast cancer
  • cancer stemness
  • drug resistance

Publisher's Copyright Statement

  • This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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