PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

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. [Display omitted] •The Akt pathway plays a critical role in resistance to tyrosine kinase inhibition•PHLDA1 is key to regulating Akt activity during the development of drug resistance•Knockdown of PHLDA1 alone confers de novo resistance to kinase inhibitors•PHLDA1 rescue resensitizes drug-resistant cancer cells 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.