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.
Subject(s)
Drug Resistance, Neoplasm , Endometrial Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Transcription Factors/metabolism , Cell Line, Tumor , Down-Regulation/drug effects , Drug Resistance, Neoplasm/drug effects , Endometrial Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Humans , Lapatinib/pharmacology , Models, Biological , Phosphoproteins/metabolism , Proteomics , Receptors, Fibroblast Growth Factor/metabolism , Transcription Factors/genetics , Trastuzumab/pharmacologyABSTRACT
The light-harvesting antenna of higher plant photosystem II has an intrinsic capability for self-defence against intense sunlight. The thermal dissipation of excess energy can be measured as the non-photochemical quenching of chlorophyll fluorescence. It has recently been proposed that the transition between the light-harvesting and self-defensive modes is associated with a reorganization of light-harvesting complexes. Here we show that despite structural changes, the photosystem II cross-section does not decrease. Our study reveals that the efficiency of energy trapping by the non-photochemical quencher(s) is lower than the efficiency of energy capture by the reaction centres. Consequently, the photoprotective mechanism works effectively for closed rather than open centres. This type of defence preserves the exceptional efficiency of electron transport in a broad range of light intensities, simultaneously ensuring high photosynthetic productivity and, under hazardous light conditions, sufficient photoprotection for both the reaction centre and the light-harvesting pigments of the antenna.
