PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2018-02-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124718301967

Summary: 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. : Fearon et al. use unbiased transcriptomic and phosphoproteomic analysis to identify PHLDA1 as a mediator of acquired resistance to kinase-targeted therapies in cancer. Using a range of cell models and clinical data, they uncover a mechanism underpinning the re-wiring of Akt signaling in cancer drug resistance. Keywords: tyrosine kinase inhibitor, drug resistance, FGF, Akt, targeted therapy, cancer