利用同步辐射红外光谱技术探索结直肠癌对EGFR单抗治疗的疗效预测及耐药机制的研究

RAS野生型肠癌患者对西妥昔单抗耐药的机制尚不明确，临床上缺乏能够精准预测西妥昔单抗治疗敏感性的可靠指标。我们在前期研究中利用同步辐射红外光谱技术（SR-FTIR）发现西妥昔单抗敏感类器官较耐药类器官出现一个饱和脂肪酸吸收峰，初步机制研究提示耐药类器官中脂肪酸的β-氧化产生乙酰CoA增加，提示脂肪酸分解利用增加可能是西妥昔单抗耐药的原因。据此，我们提出科学假设，西妥昔单抗耐药与脂肪酸代谢增加有关，细胞内通过β-氧化产生的乙酰CoA含量增高是诱导西妥昔单抗耐药的直接原因。我们将在类器官、动物模型、临床样本水平进行进一步研究：①扩大样本量行SR-FTIR技术分析，验证饱和脂肪酸吸收峰的消失与西妥昔单抗耐药相关，并进行亚细胞定位；②在类器官及动物模型中验证脂肪酸β-氧化增强可促进西妥昔单抗耐药，联合应用β-氧化抑制剂可逆转耐药；③前瞻性收集临床样本进行进一步验证，拟为逆转西妥昔单抗耐药提供新靶点

The mechanism of cetuximab resistance in RAS wild-type colorectal cancer patients is still unclear, and there is no reliable biomarker to accurately predict the sensitivity of cetuximab treatment in clinical practice. In the preliminary study, by adopting synchrotron radiation based Fourier-transform infrared (SR-FTIR) technique, we found a saturated fatty acid absorption peak in cetuximab-sensitive organoid compared with cetuximab-resistant organoid and found that the increase of acetyl CoA produced by beta-oxidation of fatty acids in cetuximab-resistant organoid may contribute to drug resistance. Based on above evidence, we hypothesize that resistance to cetuximab is related to the increase of fatty acid metabolism, and that the increase of acetyl CoA produced by intracellular beta-oxidation is the direct cause of cetuximab resistance. Further studies will be carried out towards organoid, animal model and clinical sample levels: ①Expand the sample size of SR-FTIR analysis to verify that the saturated fatty acid absorption peak is related to cetuximab resistance and verify its subcellular localization; ②Use organoid and animal models to demonstrate that enhanced fatty acid beta-oxidation can promote cetuximab resistance, and that combined use of cetuximab and beta-oxidation inhibitors can rescue cetuximab resistance. ③Prospectively collect clinical samples for further validation. Our study aims to provide a new target for reversing cetuximab resistance.