Open AccessMultidrug‐resistant transporter expression does not always result in drug resistance
Author(s) -
Le Large Tessa Ya Sung,
El Hassouni Btissame,
Kazemier Geert,
Piersma Sander R.,
Laarhoven Hanneke W. M.,
Bijlsma Maarten F.,
Jimenez Cornelia R.,
Giovannetti Elisa
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13756
Subject(s) - abcc1 , abcg2 , atp binding cassette transporter , gemcitabine , cancer research , biology , efflux , side population , population , carcinogenesis , cancer stem cell , stem cell , multiple drug resistance , transporter , cancer cell , drug resistance , pharmacology , cancer , microbiology and biotechnology , medicine , genetics , gene , environmental health
Dear Editor, With great interest, we have read the paper by Sasaki et al evaluating the role of ATP‐binding cassette (ABC) subfamily G member 2 (ABCG2) in chemoresistance and pluripotency in pancreatic ductal adenocarcinoma (PDAC). Selection for ABCG2‐positive cells did not result in increased chemoresistance, even though these cells were able to efflux fluorescent dye more efficiently than unsorted cells. Furthermore, epithelial‐to‐mesenchymal (EMT) or cancer stem cell (CSC) expression was not increased in ABCG2‐expressing cells in adherent cultures. These unexpected results indicate that the expression of ABC transporters does not always cause chemoresistance or confer stem cell‐like features, and, in fact, other mechanisms likely play an important role in the aggressive nature of PDAC. The ABC transporters have been studied extensively for their correlation between CSC and chemoresistance. Their ability to efflux xenobiotics, such as chemotherapeutics, makes them interesting targets. In our unbiased proteomic screening of a gemcitabine‐ resistant population of PANC1 cells (ATCC), we identified another ABC transporter. Cells that withstood high‐dose gemcitabine exposure showed increased ABCC1 expression and phosphorylation (Figure 1). These results led to the hypothesis that ABCC1 expression and post‐translational modification contribute to gemcitabine resistance and could be a novel target to overcome chemoresistance in PDAC. Pharmacological inhibition of ABCC1 by the drug MK‐571 in combination with gemcitabine resulted in improved sensitivity in vitro (Figure 2A). Interestingly, MK‐571 monotherapy resulted in significantly reduced viability of gemcitabine‐resistant cells (Figure 2B), suggesting additional cellular functions of ABC transporters in carcinogenesis, as described previously. Stable gene silencing of ABCC1 by shRNAs, however, did not enhance response to gemcitabine (Figure 2C). These contradictory results can be explained by functional redundancy in the ABC family and the non‐ selectivity of ABC‐targeting agents for specific ABC transporters. Together with limitations due to toxicity and adverse drug interactions, this might explain why none of the studies aimed at overcoming drug resistance by ABC members translated into successful clinical application.