Impaired cyclin D3 protein degradation contributes to trastuzumab resistance in HER2 positive breast cancer.

IF 2.8 4区 医学 Q2 ONCOLOGY Medical Oncology Pub Date : 2024-11-02 DOI:10.1007/s12032-024-02535-x
Zhuo Wang, Haiqi Lu, Yiming Zhong, Lifeng Feng, Hongchuan Jin, Xian Wang
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Abstract

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.

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细胞周期蛋白 D3 蛋白降解受损是 HER2 阳性乳腺癌产生曲妥珠单抗耐药性的原因之一。
作为美国食品及药物管理局于 1998 年批准的首个抗 HER2 靶向药物,曲妥珠单抗大大改善了 HER2 阳性转移性乳腺癌患者的预后。遗憾的是,曲妥珠单抗的耐药性是其临床应用疗效的严重障碍,其作用机制尚未完全阐明。在我们的研究中,我们发现细胞周期蛋白 D3 的稳定可能是曲妥珠单抗耐药的原因之一。曲妥珠单抗可通过下调细胞周期蛋白 D3 蛋白表达诱导 G1/G0 期停滞。然而,在曲妥珠单抗耐药细胞中,细胞周期蛋白D3的蛋白表达并未受到影响,这可能与ERK信号通路的异常激活有关。此外,曲妥珠单抗对细胞周期蛋白D3蛋白的降解主要来自泛素依赖性蛋白酶体机制,而非转录调控。在曲妥珠单抗耐药的乳腺癌细胞中,曲妥珠单抗诱导的细胞周期蛋白 D3 蛋白降解被逆转。当泛素途径受到抑制时,细胞就会对曲妥珠单抗产生抗药性。此外,CDK4/6 抑制剂还能抑制曲妥珠单抗耐药的 HER-2 阳性乳腺癌细胞的增殖。因此,CDK4/6抑制剂与抗HER2靶向疗法的结合可能是未来克服曲妥珠单抗耐药性的另一种有前途的策略。
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来源期刊
Medical Oncology
Medical Oncology 医学-肿瘤学
CiteScore
4.20
自引率
2.90%
发文量
259
审稿时长
1.4 months
期刊介绍: Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
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