结直肠癌（CRC）仍然是全球癌症相关死亡的主要原因。Cetuximab与化疗联合应用对于治疗野生型KRAS/BRAF转移性CRC（mCRC）的患者有效。然而，固有或获得性的药物耐药常限制了cetuximab的使用。在本研究中，我们研究了3-溴丙酮酸（3-BP）和cetuximab合并治疗在体外和体内克服CRC中cetuximab耐药的潜力。我们的结果表明，3-BP和cetuximab的联合治疗在具有固有cetuximab耐药性的CRC细胞系（DLD-1（KRASG13D/-）和HT29（BRAFV600E））以及从Caco-2中获得耐药的耐cetuximab细胞系（Caco-2-CR）中，协同诱导了抗增殖效应。进一步分析揭示了联合治疗诱导了铁死亡、自噬和凋亡。在机制上，联合治疗抑制了FOXO3a的磷酸化和降解，并激活了FOXO3a/AMPKα/pBeclin1和FOXO3a/PUMA通路，导致了DLD-1（KRASG13D/-）、HT29（BRAFV600E）和Caco-2-CR细胞中铁死亡、自噬和凋亡的促进。总之，我们的发现表明，3-BP和cetuximab的联合治疗可能是克服人类CRC中cetuximab耐药的有希望的策略。© 2023. 作者。

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Cetuximab, in combination with chemotherapy, is effective for treating patients with wild-type KRAS/BRAF metastatic CRC (mCRC). However, intrinsic or acquired drug resistance often limits the use of cetuximab. In this study, we investigated the potential of co-treatment with 3-Bromopyruvate (3-BP) and cetuximab to overcome cetuximab resistance in CRC, both in vitro and in vivo. Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines with intrinsic cetuximab resistance (DLD-1 (KRASG13D/-) and HT29 (BRAFV600E)) and in a cetuximab-resistant cell line derived from Caco-2 with acquired resistance (Caco-2-CR). Further analysis revealed that co-treatment induced ferroptosis, autophagy, and apoptosis. Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRASG13D/-), HT29 (BRAFV600E), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.© 2023. The Author(s).