Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Obstetrics and Gynecology, Zhongshan Hospital, Shanghai 200032, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Jun 13;55(9):1467-1478. doi: 10.3724/abbs.2023111.
The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to mutation and demonstrates a prognostic role in CRC patients with mutation. Thus, ACAA2 is a potential target in CRC with mutation.
抗 EGFR 治疗的出现彻底改变了结直肠癌（CRC）的治疗方法。然而，并非所有患者的反应都一致良好。因此，必须进行进一步的研究，以确定 CRC 中导致西妥昔单抗耐药的分子机制。在这项研究中，我们发现与敏感细胞相比，西妥昔单抗耐药 CRC 细胞中许多代谢相关基因的表达下调。具体来说，在西妥昔单抗耐药性的发展过程中，乙酰辅酶 A 酰基转移酶 2（ACAA2）是脂肪酸代谢的关键酶，其表达下调。沉默 可促进 CRC 细胞的增殖并增加西妥昔单抗耐受性，而 ACAA2 的过表达则产生相反的效果。RTK-Kras 信号可能导致 CRC 中 ACAA2 表达下调，并且 ACAA2 可预测 突变患者的 CRC 预后。总之，我们的数据表明，调节 ACAA2 的表达有助于 Kras 野生型 CRC 患者的继发西妥昔单抗耐药性。ACAA2 的表达与 突变有关，并在 突变的 CRC 患者中具有预后作用。因此，ACAA2 是 突变的 CRC 的潜在治疗靶点。
