Abstract
Molecular and metabolic alterations in cancer cells are one of the leading causes of acquired resistance to chemotherapeutics. In this study, we explored an experimental strategy to identify which of these alterations can induce erlotinib resistance in human pancreatic cancer. Using genetically matched erlotinib-sensitive (BxPC-3) and erlotinib-resistant (BxPC-3ER) pancreatic cancer cells, we conducted a multi-omics analysis of metabolomes and transcriptomes in these cells. Untargeted and targeted metabolomic analyses revealed significant changes in metabolic pathways involved in the regulation of polyamines, amino acids, and fatty acids. Further transcriptomic analysis identified that ornithine decarboxylase (ODC) and its major metabolite, putrescine, contribute to the acquisition of erlotinib resistance in BxPC-3ER cells. Notably, either pharmacological or genetic blockage of ODC was able to restore erlotinib sensitivity, and this could be rescued by treatment with exogenous putrescine in erlotinib-resistant BxPC-3ER cells. Moreover, using a panel of cancer cells we demonstrated that ODC expression levels in cancer cells are inversely correlated with sensitivity to chemotherapeutics. Taken together, our findings will begin to uncover mechanisms of acquired drug resistance and ultimately help to identify potential therapeutic markers in cancer.
Highlights
Pancreatic cancer is one of the most fatal diseases, with an annual incidence that almost equals its annual mortality rate [1, 2]
BxPC-3ER cells displayed increased invasiveness through Matrigel compared to BxPC-3 cells. These results indicate that erlotinib-resistant BxPC-3ER cells exhibit enhanced anchorage-independent cell growth and invasiveness versus their parental cells, suggesting a close correlation between erlotinib resistance and metastatic potential in BxPC-3ER cells
Consistent with this, qRT-PCR (Figure 1F) and western blot analysis (Figure 1G) confirmed the expression of E-cadherin and Snail1, a transcriptional repressor of E-cadherin, in both BxPC-3 and BxPC-3ER cells. These data suggest that acquired resistance to erlotinib in BxPC-3ER cells might be associated with attained epithelial-mesenchymal transition (EMT) properties
Summary
Pancreatic cancer is one of the most fatal diseases, with an annual incidence that almost equals its annual mortality rate [1, 2]. Combination therapies using erlotinib, a small molecule tyrosine kinase inhibitor of EGFR (EGFR-TKI), together with gemcitabine, has been clinically approved for the treatment of both unresectable locally advanced and metastatic pancreatic cancer. This regimen has prolonged the median survival time of patients with pancreatic cancer, it has limited therapeutic benefits because 25-30% of patients became drug-resistant after only a short course of therapy [6,7,8]
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