Abstract 4737: IGF and insulin system in regulating hallmarks of cancer

The Insulin-like growth factor (IGF) and insulin system is implicated in various cancers and is known to regulate cell growth, proliferation, and metabolism. Type 1 IGF receptor (IGF-1R) targeting strategies have been unsuccessful, probably due to its characteristic to form heterotetrameric hybrids with the homologous insulin receptor (IR). This introduces multiple IGF-1 binding sites and draws focus on IR and its isoforms - IR-A and IR-B, as potential therapeutic targets. A high IR-A to IR-B ratio is observed in tumors including breast cancer. IR-A regulates fetal growth and development while IR-B is predominantly found in the liver and skeletal muscle where glucose uptake is regulated via glucose transporter GLUT4. Non-specific IR targeting likely leads to metabolic imbalance and thus necessitates delineating IR isoform roles to develop efficient targeted strategies. Ideally, targeting IR-A specifically, and leaving IR-B unaffected, might be an effective IGF and insulin system targeting approach. Our group developed IR K/O MCF-7L (ER+ breast cancer cell line) and introduced IR-A or IR-B to generate isoform-specific cell lines. The real-time ATP production rates suggest IGF-1 promotes glycolytic ATP production in MCF-7L, MDA MB 231, MCF-7L IR K/O, and MCF-7L IR-B K/I while insulin at physiological concentration doesn’t affect ATP production. Therefore, IR-B may maintain the metabolic demand of ER+ breast cancer cells when activated by IGF-1. Additionally, IR inactivation and metabolic stimulation via IGF-1 suggest investigating alternative fuels to glucose. Our group previously showed IGF-1 activates cystine/glutamate transporter: xC-, in ER+ cells through PI3K/Akt signaling, sequentially regulating ROS. This further supports proliferation, metastasis, and drug resistance. Glutamine is the rate-limiting step for this transporter exchange and hence a potential candidate driving the observed glycolytic phenotype. Preliminary data suggests MCF-7L maintains the metabolic demand through glucose and glutamine when stimulated with IGF-1. IGF-1 also stimulated migration in MCF-7L and MDA MB 231 cell lines while insulin promoted this phenotype in MDA MB 231 only. This suggests that the IGF and insulin system maintains the metabolic demand of cancer cells to promote cancer aggressiveness. Further investigation will elucidate IR isoform roles in cellular hallmarks of cancer. Citation Format: Bhumika Rajoria, Douglas Yee. IGF and insulin system in regulating hallmarks of cancer [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 4737.