Abstract 415: Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small lung cancer

Abstract Acquired resistance represents a bottleneck to molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer, but its role in acquired resistance has not been fully understood. In this study, we discovered a novel mechanism of TKI resistance involved in IGF2BP3-dependent crosstalk between the epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis. We demonstrated the upregulated expression of RNA binding protein IGF2BP3 reduced the sensitivity of TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). Analysis of patient samples revealed a positive correlation between IGF2BP3 and COX6B2 and poor prognosis in lung cancer patients. We further confirmed that COX6B2 is a key downstream target in IGF2BP3-mediated acquired TKI-resistance. Mechanistically, IGF2BP3 bound to the 3’-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, IGF2BP3 significantly enhanced OXPHOS capacity in lung cancer through the IGF2BP3-COX6B2 axis by regulating nicotinamide metabolism, thus resulting in TKI resistance in lung cancer. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in remarkable growth inhibition in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, our findings suggest that metabolic reprogramming directed by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance, and targeting the metabolic pathway provides a new therapeutic strategy to overcome EGFR-TKI resistance in lung cancer. Citation Format: Ziyou Lin, Jingwei Li, Jian Zhang, Weineng Feng, Jiaye Lu, Xiaofan Ma, Wen Ding, Shumin Ouyang, Jinjian Lu, Peibin Yue, Guohui Wan, Peiqing Liu, Xiaolei Zhang. Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 415.