Nutrient-Dependency of CendR Endocytosis Pathway is Uniquely Regulated by Mutant Kras and Targetable

Abstract

Kras is the hallmark mutation of Pancreatic Ductal Adenocarcinoma (PDAC) and reprograms tumor metabolism towards glycolysis. Evolutionarily, PDAC instigates diabetes to increase glucose concentrations and fuel tumor growth. The C-end Rule (CendR)-pathway mediates nutrient endocytotic transcytosis and trans-tissue molecular transport. A discrepancy exists in that the CendR pathway is primed to high activity when glucose is low. Ongoing PDAC clinical trials utilize tumor-penetrating peptides (iRGD) to activate the CendR-pathway and dispense cargo. Here, we determine how glucose metabolism changes based on tumor Kras-status might affect the CendR pathway and hijack it to deliver therapy. Under diabetic-like conditions, iRGD increases its penetration and spread throughout patient-derived and mouse PDAC. Importantly, all CendR peptides delivered higher concentrations of co-administered therapeutic cargo in a glucose-dependent manner. Neuropilin-1 (NRP-1), the receptor for peptide-mediated activation of the CendR pathway, is expressed in greater abundance under high glucose concentrations in parallel with glycolytic machinery. Hypoglycemic Kras-mutant tumors, hyperglycemic Kras-wildtype tumors, and inhibition of the mitogen-activated protein kinase (MAPK) pathway all suppressed NRP-1, CendR-peptide transport, and cargo uptake. Overall, mutant Kras enhances CendR peptide-directed cargo delivery in glycolytic metabolic environments via NRP-1 expression. Manipulating patient blood glucose levels may enhance CendR-based targeting of therapeutics into Kras-mutant tumors.