PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer

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 down-regulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using FGFR inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by down-regulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 down-regulation 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-sensitised 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.

OTHER RELATED OMICS DATASETS IN: PRJNA320773

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cancer

SUBMITTER: Vinothini Rajeeve  

LAB HEAD: Dr Pedro Cutillas

PROVIDER: PXD008859 | Pride | 2018-03-05

REPOSITORIES: Pride