De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

Abstract

Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single agent therapy for pancreatic cancer. While the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging TCGA dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of ER stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness.

Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition

“…Biosynthesis of heme and several phospholipid molecules were pathways uniquely associated with resistance to our nucleoside analogs. Both of these metabolic pathways have been described as important mechanisms of gemcitabine resistance and likely play a role in oxidative stress response (Miyake et al, 2010;Tadros et al, 2017). Overall, we saw that there was a weak positive correlation between enrichment across our screens and patient survival.…”

Metabolic Alterations in Pancreatic Cancer Progression

“…Our lab demonstrated that by increasing glucose uptake and metabolic flux through the non-oxidative arm of pentose phosphate pathway, gemcitabine-resistant cancer cells increase pyrimidine synthesis which competes with gemcitabine incorporation [20]. Furthermore, we showed how pancreatic cancer relies on fatty acids biosynthesis for gemcitabine resistance [46]. A different approach to reduce gemcitabine resistance is through a glutamine analog.…”

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

“…The palmitate generated through de novo synthesis has a number of intracellular functions, including regulation of signaling networks in PDA and perturbations at multiple steps (ACC, FASN) attenuates PDA growth [83]. It has been recently reported that high FASN expression correlates with gemcitabine resistance in PDA and combination treatment of Orlistat (FASN inhibitor) and gemcitabine results in a synergistic response [84]. …”