PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

Abbie E Fearon, Edward P Carter, Natasha S Clayton, Edmund H Wilkes, Ann-Marie Baker, Ekaterina Kapitonova, Bakhouche A Bakhouche, Yasmine Tanner, Jun Wang, Emanuela Gadaleta, Claude Chelala, Kate M Moore, John F Marshall, Juliette Chupin, Peter Schmid, J Louise Jones, Michelle Lockley, Pedro R Cutillas, Richard P Grose

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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+ 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.

Original languageEnglish
Pages (from-to)2469-2481
Number of pages13
JournalCell Reports
Volume22
Issue number9
Early online date27 Feb 2018
DOIs
Publication statusPublished - 27 Feb 2018

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