Abstract 2818: Targeting PIKfyve sensitizes gastroenteropancreatic neuroendocrine tumor to mTOR inhibition by disrupting ferritinophagy and lipid homeostasis

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown a significant global increase over the past decade. The mTOR signaling pathway is a positive regulator of cell cycle progression, with its activation playing a key role in the pathogenesis of NETs. Since 2011, the FDA-approved mTOR inhibitor everolimus has been used as an anti-tumor agent for treating progressive NETs, and its clinical efficacy is limited due to rapid disease relapse and progression. In this study, we investigated the role of autophagy, specifically ferritinophagy, in mediating resistance to mTOR inhibition in GEP-NETs. Enhanced ferritinophagy followed by mTOR inhibition increases intracellular iron availability, supporting tumor cell energy production and survival. Genetic or pharmacological inhibition of PIKfyve, a lipid kinase integral to lysosomal functioning, disrupted ferritinophagy, reducing the intracellular iron pool elevated by mTOR inhibition. Interestingly, mTOR inhibition also restored cholesterol and fatty acid biosynthesis resulting from PIKfyve inhibition. Notably, dual inhibition of mTOR and PIKfyve exhibited a strong synergistic antitumor effect in vitro and significantly prolonged survival in an orthotopic GEP-NET preclinical model. Together, our findings highlight the therapeutic potential of combining mTOR and PIKfyve inhibitors in the treatment of GEP-NETs. Citation Format: Yizhi Cao, Yitong Yin, Caleb Cheng, Shannon VanAkon, Sarah Nicole Yee, Jacinda Jiali Liu, Yang Zheng, Andrej Coleski, Radha Paturu, Somnath Mahapatra, Fan Yang, Rupam Bhattacharyya, Rahul Mannan, Yuanyuan Qiao, Arul Chinnaiyan. Targeting PIKfyve sensitizes gastroenteropancreatic neuroendocrine tumor to mTOR inhibition by disrupting ferritinophagy and lipid homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2818.