Abstract
Aim: Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma (PDAC), but neither gemcitabine alone nor in combination produces durable remissions of this tumor type. We developed three PDAC patient-derived xenograft (PDX) models with gemcitabine resistance (gemR) acquired in vivo, with which to identify mechanisms of resistance relevant to drug exposure in vivo and to evaluate novel therapies.Methods: Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly. Tumors initially responded, but regrew on treatment and were designated gemR. We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance [ribonucleotide reductase subunit M1 (RRM1), RRM2, human concentrative nucleoside transporter 1 (hCNT1), human equilibrative nucleoside transporter 1 (hENT1), cytidine deaminase (CDA), and deoxycytidine kinase (dCK)] in gemR and respective gemcitabine-naïve parental tumors.Results: Parental and gemR tumors did not differ in tumor cell morphology, amount of tumor-associated stroma, or expression of stem cell markers. No consistent pattern of expression of the six gemR marker proteins was observed among the models. Increases in RRM1 and CDA were consistent with in vitro-derived gemR models. However, rather than the expected decreases of hCNT1, hENT1, and dCK, gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors.Conclusion: These models are the first PDAC PDX models with gemcitabine resistance acquired in vivo. The data indicate that mechanisms identified in models with resistance acquired in vitro are unlikely to be the predominant mechanisms when resistance is acquired in vivo. Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models.
Highlights
Pancreatic cancer remains one of the few solid tumors with a five-year survival less than 10%[1]
These models are the first Pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) models with gemcitabine resistance acquired in vivo
We developed patient-derived xenograft (PDX) models derived from primary human tumors with resistance acquired in vivo, as tools to identify which resistance mechanisms in cell line-based models occur in models designed to reflect in vivo responses to gemcitabine
Summary
Pancreatic cancer remains one of the few solid tumors with a five-year survival less than 10%[1]. Most PDAC patients present with locally advanced or metastatic disease, prognostic indicators for unfavorable outcome. Surgical resection is potentially curative, but few patients present with resectable disease. For most patients with nonresectable disease, gemcitabine-based therapies have been standard of care agents for more than two decades[3,4,5]. Numerous studies focused on identifying molecular bases for gemcitabine resistance have been equivocally successful in designing effective therapies. One of the latest reports by Cascioferro et al.[10] documented an interesting note that some of imidazo [2,1-b][1.3.4] thiadiazole derivatives showed low micromolar antiproliferative activity against gemcitabine resistant Panc-1 pancreatic cancer cells (Panc-1R) in vitro. The authors showed that a potential mechanism of these derivatives could be inhibition of phosphorylation of PTK2/ FAK
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