Erlotinib in Combination with Capecitabine (5'dFUR) in Resistant Pancreatic Cancer Cell Lines

Abstract

The combination of capecitabine and the tyrosine kinase inhibitor erlotinib has recently been tested in patients with gemcitabine-refractory pancreatic tumors, with limited success. To understand this lack of efficacy, we studied the molecular effects of these agents in Capan-1 and Capan-2 human pancreatic resistant cancer cells. Erlotinib up-regulated thymidine phosphorylase (+50%) and downregulated dihydropyrimidine dehydrogenase (+55%) in a cell-dependent manner, thus suggesting that the combination should result in synergism. However, only mild additivity was achieved at best when combining both drugs, and several sequences tested even led to strong antagonism. Further experiments were performed to understand this lack of efficacy. We found that the fluoropyrimidine down-regulated EGFR expression by 30%, an unexpected finding resulting in a possible reduction in efficacy when cells were subsequently exposed to erlotinib. We also observed marked drug-induced over-expression of both cytosolic and extracellular vascular endothelial growth factor (VEGF) secretion, thus possibly triggering proliferation. These preliminary findings strongly suggest that these observations could be new mechanisms in the development of acquired drug resistance in pancreatic cancer cells.

Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer

“…Erlotinib is a small molecule EGFR‐TKI, and its integration with gemcitabine‐based chemotherapy has a statistically significant survival benefit over gemcitabine alone for treatment of advanced PC in a double‐blind, international phase III trial . Unfortunately, the resistance of PC cells to erlotinib was developed and sharply decreased the clinical outcomes of advanced/metastatic PC patients . K‐RAS ‐mutated PC cells lines MiaPaCa‐2, Panc‐1 and AsPc‐1 were reported to display the intense resistance to erlotinib .…”

“…Erlotinib, a small molecule EGFR‐tyrosine kinase inhibitor (EGFR‐TKI), can effectively improve the clinical efficacy of gemcitabine‐based chemotherapies in the treatment of advanced PC, as shown by improving overall survival and clinical benefit response . However, the clinical application of erlotinib is limited by the resistance of PC cells to erlotinib as evidenced by the findings that erlotinib in combination with capecitabine led to a 10% objective response rate . Overcoming erlotinib resistance has become a critical issue for improving the outcome of PC chemotherapy.…”

Modeling the Impact of Anticancer Agents on Metastatic Spreading

“…Our model is thus designed to take into account for the possible counter-attack of tumor cells towards AA therapy, as suggested by [20] and shown in [15]. Indeed, in this last paper the authors demonstrate an increase of VEGF tumoral expression after erlotinib therapy in an in vitro experiment.…”

Phase I Trial of Gemcitabine Combined with Capecitabine and Erlotinib in Advanced Pancreatic Cancer: A Clinical and Pharmacological Study

“…A phase III clinical trial demonstrated that erlotinib associated with gemcitabine potentiates gemcitabine-induced apoptosis as compared to gemcitabine alone [19]. An experimental study by our group has been conducted on human pancreatic cancer cell lines showing that erlotinib significantly increases thymidine phosphorylase activity by 50%, while it decreases DPD activity by 55% [20]. Taken together, these data provide a strong pharmacologic rationale for combining erlotinib with capecitabine in pancreatic tumors, since they suggest that the gemcitabine-erlotinib combination may result in a drug effect synergism [20].…”

“…An experimental study by our group has been conducted on human pancreatic cancer cell lines showing that erlotinib significantly increases thymidine phosphorylase activity by 50%, while it decreases DPD activity by 55% [20]. Taken together, these data provide a strong pharmacologic rationale for combining erlotinib with capecitabine in pancreatic tumors, since they suggest that the gemcitabine-erlotinib combination may result in a drug effect synergism [20]. A very recent phase II trial pointed out promising antitumor activity of gemcitabine associated with capecitabine and erlotinib in previously untreated metastatic pancreatic cancer, excluding locally advanced cancer [21].…”