尽管实施了个体化医疗，但由于获得性耐药机制频繁发生从而导致临床复发，转移性结直肠癌（mCRC）患者的总生存率仍然很低。因此，了解支持 mCRC 抗 EGFR 靶向治疗获得性耐药的分子机制具有临床相关性，也是改善患者预后的关键。在这里，我们观察到西妥昔单抗耐药性 CRC 细胞群之间存在明显的代谢变化，特别是 KRAS 突变的西妥昔单抗耐药性 CRC 细胞（LIM1215 和 OXCO2）中糖酵解活性增加，但 KRAS 扩增的耐药 DiFi 细胞中糖酵解活性没有增加。我们证明，西妥昔单抗耐药的 LIM1215 和 OXCO2 细胞具有回收糖酵解衍生的乳酸以维持其生长能力的能力。这与乳酸输入蛋白 MCT1 在转录物和蛋白质水平上的上调有关。 AR-C155858 对 MCT1 的药理学抑制可减少乳酸的摄取和氧化，并损害西妥昔单抗耐药 LIM1215 细胞的体外和体内生长能力。这项研究将 MCT1 依赖性乳酸利用确定为临床上可行的代谢脆弱性，以克服 CRC 中 KRAS 突变介导的抗 EGFR 治疗获得性耐药性。版权所有 © 2024。由 Elsevier B.V 出版。

Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant CRC cells (LIM1215 and OXCO2) but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 and OXCO2 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells both in vitro and in vivo. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.Copyright © 2024. Published by Elsevier B.V.