PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer.

Cell Reports
Abbie E FearonRichard P Grose

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.

Citations

Sep 13, 2018·Cancer Science·Yu ChenRieko Ohki
Mar 20, 2019·International Journal of Molecular Sciences·Marek GowkielewiczMarta Majewska
Jun 19, 2019·Nature Methods·Christopher S McGinnisZev J Gartner
Mar 21, 2019·Biopolymers·Konstantin AndreevDavid Gidalevitz
May 21, 2020·International Journal of Molecular Sciences·Taylor T Fuselier, Hua Lu
Feb 12, 2021·Journal of Hematology & Oncology·Sitong YueDaichao Wu

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Datasets Mentioned

BETA
GSE81169

Methods Mentioned

BETA
transfection
xenograft
electrophoresis

Software Mentioned

Illumina Genome Studio

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