Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase
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Metabolic plasticity imparts erlotinibresistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase Neha Sharma1, Alok Bhushan1, Jun He2, Gagan Kaushal1 and Vikas Bhardwaj1*
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinibresistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/ NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance. Keywords: Erlotinib resistance, Metabolic reprogramming, Pancreatic cancer
Introduction Epidermal growth factor receptor (EGFR), first described in the early 1980s, is a transmembrane tyrosine kinase receptor that is deregulated in various tumors [1, 2]. Upregulation or mutation of EGFR has been associated with the progression of non-small cell lung carcinoma (NSCLC), pancreatic cancers, colorectal cancers, and glioblastomas, among other tumors. EGFR-targeted therapies, including monoclonal antibodies (e.g., cetuximab) * Correspondence: [email protected] 1 Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA Full list of author information is available at the end of the article
and small molecule inhibitors (e.g., erlotinib, gefitinib), have become valuable therapeutic tools. Small molecule inhibitors of EGFR have especially been beneficial for NSCLC and pancreatic ductal adenocarcinoma (PDAC) patients. PDAC is one of the most malignant forms of cancer with an overall 5-year survival rate of 8%. With approximately 44,300 deaths in the year 2018, it is the third leading cause of cancer-related deaths in the USA [3]. Late diagnosis, lack of effective treatment options, and drug resistance mak
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