Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Med Oncol. 2024 Nov 2;41(12):305. doi: 10.1007/s12032-024-02535-x.
As the first anti-HER2 targeted agent approved by FDA in 1998, Trastuzumab has significantly improved the outcome of patients with HER2 positive metastatic breast cancer. Unfortunately, resistance to trastuzumab is a severe obstacle to its therapeutic efficacy in clinical application, and its mechanism has not yet been fully elucidated. In our study, we found that stabilization of cyclin D3 could be one reason for trastuzumab resistance. Trastuzumab could induce G1/G0 phase arrest by downregulating cyclin D3 protein expression. However, the protein expression of cyclin D3 was not affected in trastuzumab-resistant cells, which might be related to aberrant activation of ERK signaling pathway. Furthermore, degradation of cyclin D3 protein by trastuzumab was mainly resulted from ubiquitin-dependent proteasome mechanism instead of transcriptional regulation. In trastuzumab-resistant breast cancer cells, trastuzumab-induced degradation of cyclin D3 protein was abrogated. When the ubiquitin pathway was inhibited, cells would show a predisposition to resistance to trastuzumab. Further, CDK4/6 inhibitor can inhibit the proliferation of trastuzumab-resistant HER-2 positive breast cancer cells. Therefore, combination of CDK4/6 inhibitors and anti-HER2 targeted therapy may be an alternative and promising strategy to overcome trastuzumab resistance in the future.
作为 1998 年 FDA 批准的首个抗 HER2 靶向药物，曲妥珠单抗显著改善了 HER2 阳性转移性乳腺癌患者的预后。不幸的是，曲妥珠单抗耐药是其临床应用疗效的严重障碍，其机制尚未完全阐明。在我们的研究中，我们发现 cyclin D3 的稳定可能是曲妥珠单抗耐药的一个原因。曲妥珠单抗可以通过下调 cyclin D3 蛋白表达诱导 G1/G0 期阻滞。然而，曲妥珠单抗耐药细胞中 cyclin D3 的蛋白表达不受影响，这可能与 ERK 信号通路的异常激活有关。此外，曲妥珠单抗诱导 cyclin D3 蛋白降解主要是通过泛素依赖性蛋白酶体机制，而不是转录调控。在曲妥珠单抗耐药的乳腺癌细胞中，曲妥珠单抗诱导的 cyclin D3 蛋白降解被阻断。当抑制泛素途径时，细胞对曲妥珠单抗的耐药性会增加。此外，CDK4/6 抑制剂可以抑制曲妥珠单抗耐药的 HER-2 阳性乳腺癌细胞的增殖。因此，联合 CDK4/6 抑制剂和抗 HER2 靶向治疗可能是未来克服曲妥珠单抗耐药的一种替代和有前途的策略。
