PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer | Zendy

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

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PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

Author(s) -

Abbie E. Fearon,

Edward Carter,

Natasha S. Clayton,

Edmund H. Wilkes,

AnnMarie 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 Grose

Publication year - 2018

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2018.02.028

Subject(s) - downregulation and upregulation , protein kinase b , receptor tyrosine kinase , cancer research , tyrosine kinase , drug resistance , cancer , biology , signal transduction , pharmacology , microbiology and biotechnology , biochemistry , genetics , gene

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.

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