Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression
Medical weight loss is becoming increasingly prevalent, but impacts on cancer remain unclear. We report that in mice with significant retatrutide (RETA, LY3437943)-induced weight loss, reduced food intake, and improved glucose tolerance and other metabolic parameters, subsequent obesity-associated pancreatic cancer engraftment was reduced, and tumor onset was delayed, with blunted progression resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Interestingly, when RETA was withdrawn before tumor implantation, the anti-tumor benefits of RETA persisted with reduced tumor burden despite weight regain. RETA induced durable anti-tumor immunity evidenced by activation of pro-inflammatory pathways in the tumor microenvironment. These findings suggest that patients with RETA-mediated weight loss may benefit from reduced cancer risk and improved outcomes. Overall design: Bulk RNA -Seq data from tumor (subcutaneously injected with KPCY Pancreatic Cancer Cells) in obese C57BL/6J mice, treated with vehicle (water, N = 10), RETA (N = 12), or RETA-withdrawal (switched from RETA to water after stabilized weight loss, N = 14), grown for 18 days, excised and snap frozen.