Multi-omics analysis reveals that ornithine decarboxylase contributes to erlotinib resistance in pancreatic cancer cells

// Won-Jun Jang 1, * , Boyeon Choi 1, * , Sang-Hoon Song 1 , Naeun Lee 1 , Dong-Joon Kim 2 , Sooyeun Lee 1 and Chul-Ho Jeong 1 1 College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea 2 China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China * These authors have contributed equally to this work Correspondence to: Sooyeun Lee, email: sylee21@kmu.ac.kr Chul-Ho Jeong, email: chjeong75@kmu.ac.kr Keywords: resistance, erlotinib, pancreatic cancer, metabolomics, ornithine decarboxylase Received: August 06, 2017      Accepted: September 04, 2017      Published: October 06, 2017 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.