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<p>Medical therapeutics for weight loss are changing the landscape of obesity but impacts on obesity-associated cancer remain unclear. We report that in pre-clinical models with significant retatrutide (RETA, LY3437943)-induced weight loss, pancreatic cancer engraftment was reduced, tumor onset was delayed, and progression was attenuated resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Despite weight re-gain after RETA withdrawal, the anti-tumor benefits of RETA persisted. Remarkably, RETA-induced protection extends to a lung cancer model with 50% reduced tumor engraftment, significantly delayed tumor onset, and mitigated tumor progression, with a 17-fold reduction in tumor volume compared to controls. RETA induced immune reprogramming systemically and in the tumor microenvironment with durable anti-tumor immunity evidenced by elevated circulating IL-6, increased antigen presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways. In sum, our findings suggest that patients with RETA-mediated weight loss may also benefit from reduced cancer risk and improved outcomes.</p>

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Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月14日

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  • Sandesh J. Marathe,
  • Emily W. Grey,
  • Margaret S. Bohm,
  • Sydney C. Joseph,
  • Arvind V. Ramesh,
  • Matthew A. Cottam,
  • Kamran Idrees,
  • Kathryn E. Wellen,
  • Alyssa H. Hasty,
  • Jeffrey C. Rathmell,
  • Liza Makowski

摘要

Medical therapeutics for weight loss are changing the landscape of obesity but impacts on obesity-associated cancer remain unclear. We report that in pre-clinical models with significant retatrutide (RETA, LY3437943)-induced weight loss, pancreatic cancer engraftment was reduced, tumor onset was delayed, and progression was attenuated resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Despite weight re-gain after RETA withdrawal, the anti-tumor benefits of RETA persisted. Remarkably, RETA-induced protection extends to a lung cancer model with 50% reduced tumor engraftment, significantly delayed tumor onset, and mitigated tumor progression, with a 17-fold reduction in tumor volume compared to controls. RETA induced immune reprogramming systemically and in the tumor microenvironment with durable anti-tumor immunity evidenced by elevated circulating IL-6, increased antigen presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways. In sum, our findings suggest that patients with RETA-mediated weight loss may also benefit from reduced cancer risk and improved outcomes.