期刊
CELL REPORTS
卷 22, 期 9, 页码 2469-2481出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.02.028
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资金
- Cancer Research UK [C16420/A12995]
- Barry Reed Research Fund [576/2334SPF1001]
- Breast Cancer Now [PR052]
- CRUK/DH Barts Experimental Cancer Medicine Centre [C16420/A15583]
- Cancer Research UK Centre Grant [C16420/A18066]
- Barts Charity [MGU0263] Funding Source: researchfish
- Cancer Research UK [19694, 13034] Funding Source: researchfish
- BBSRC [BB/M006174/1] Funding Source: UKRI
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 resensitized 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.
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