TY - JOUR
T1 - Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment
AU - le Large, Tessa Ya Sung
AU - el Hassouni, Btissame
AU - Funel, Niccola
AU - Kok, Bart
AU - Piersma, Sander R.
AU - Pham, Thang V.
AU - Olive, Kenneth P.
AU - Kazemier, Geert
AU - van Laarhoven, Hanneke W. M.
AU - Jimenez, Connie R.
AU - Bijlsma, Maarten F.
AU - Giovannetti, Elisa
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066870862&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31205498
U2 - https://doi.org/10.1177/1758835919841233
DO - https://doi.org/10.1177/1758835919841233
M3 - Article
C2 - 31205498
SN - 1758-8340
VL - 11
JO - Therapeutic advances in medical oncology
JF - Therapeutic advances in medical oncology
ER -