期刊
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
卷 11, 期 -, 页码 -出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1758835919841233
关键词
gemcitabine; nab-paclitaxel; pancreatic cancer; phosphoproteomics; proteomics; resistance
类别
资金
- Cancer Center Amsterdam(Alliantie-AIO grant, the Netherlands)
- Bennink Foundation (the Netherlands)
- Italian Association for Cancer Research (AIRC/Start-Up, Italy)
- Lisa Waller Hayes Foundation (the Netherlands)
- KWF Dutch Cancer Society (the Netherlands) [10212, 10401]
- NIH [1R01CA215607, 1R21CA188857]
Background: Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). Here we aimed to evaluate the (phospho)proteome of gemcitabine-sensitive and gemcitabine-resistant PDAC cells to identify novel therapeutic targets and predictive biomarkers. Methods: The oncogenic capabilities of gemcitabine-sensitive and resistant PDAC cells were evaluated in vitro and in vivo. Cultured cells were analyzed by label-free proteomics. Differential proteins and phosphopeptides were evaluated by gene ontology and for their predictive or prognostic biomarker potential with immunohistochemistry of tissue microarrays. Results: Gemcitabine-resistant cells had increased potential to induce xenograft tumours (p value < 0.001). Differential analyses showed that proteins associated with gemcitabine resistance are correlated with microtubule regulation. Indeed, gemcitabine-resistant cells displayed an increased sensitivity for paclitaxel in vitro (p < 0.001) and nab-paclitaxel had a strong anti-tumour efficacy in vivo. Microtubule-associated protein 2 (MAP2) was found to be highly upregulated (p = 0.002, fold change = 10) and phosphorylated in these resistant cells. Expression of MAP2 was correlated with a poorer overall survival in patients treated with gemcitabine in the palliative (p = 0.037) and adjuvant setting (p = 0.014). Conclusions: These data show an explanation as to why the combination of gemcitabine with nab-paclitaxel is effective in PDAC patients. The identified gemcitabine-resistance marker, MAP2, emerged as a novel prognostic marker in PDAC patients treated with gemcitabine and warrants further clinical investigation.
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