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PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer.
- Source :
-
Cell reports [Cell Rep] 2018 Feb 27; Vol. 22 (9), pp. 2469-2481. - Publication Year :
- 2018
-
Abstract
- Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2 <superscript>+</superscript> breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.<br /> (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Line, Tumor
Down-Regulation drug effects
Endometrial Neoplasms pathology
Female
Gene Expression Regulation, Neoplastic drug effects
Gene Knockdown Techniques
Humans
Lapatinib pharmacology
Models, Biological
Phosphoproteins metabolism
Proteomics
Receptors, Fibroblast Growth Factor metabolism
Transcription Factors genetics
Trastuzumab pharmacology
Drug Resistance, Neoplasm drug effects
Endometrial Neoplasms metabolism
Protein Kinase Inhibitors pharmacology
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 22
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 29490281
- Full Text :
- https://doi.org/10.1016/j.celrep.2018.02.028