随着抗 HER2 疗法的发展，HER2 阳性乳腺癌 (BC) 的预后有所改善；然而，问题依然存在，仍然存在抗 HER2 疗法反应不佳的情况。我们发现甲羟戊酸途径中的主要转录因子 SREBF2 的表达与 ERBB2 (HER2) 的表达以及 HER2 阳性 BC 的不良预后相关。 SREBF2 的靶基因表达与 HER2 阳性 BC 细胞中 ERBB2 的较高表达相关。他汀类药物是抑制甲羟戊酸途径的抗高胆固醇血症药物，可增强 HER2 靶向药物的功效，并以香叶基香叶基化依赖性方式诱导细胞凋亡。从机制上讲，他汀类药物特异性抑制香叶基香叶基化的靶蛋白 Rac1 的膜定位，并抑制 HER2 下游 AKT 和 ERK 通路的激活。回顾性分析一致显示，与不使用他汀类药物相比，使用 HER2 靶向药物和他汀类药物治疗的 Rac1 高/HER2 阳性 BC 患者的无复发生存期更长。因此，我们的研究结果表明，Rac1 表达可用作对 HER2 阳性 BC 患者进行分层的生物标志物，这些患者可受益于双重阻断，即使用他汀类药物抑制 Rac1 的香叶基香叶基化来靶向 HER2，从而为新子集中的精准医疗开辟途径Rac1-high/HER2-positive BC。版权所有 © 2024。由 Elsevier B.V. 出版

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.Copyright © 2024. Published by Elsevier B.V.