Preclinical and Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
Cancer Res. 2022 Dec 16;82(24):4670-4679. doi: 10.1158/0008-5472.CAN-22-0787.
Antibody-drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression.
Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells.
抗体药物偶联物（ADC）是最近引入抗肿瘤武器库的抗肿瘤药物。T-DM1 是一种基于曲妥珠单抗的 ADC，依赖于溶酶体处理来释放有效载荷，用于治疗 HER2 阳性乳腺癌。针对 HER2 的下一代 ADC，如[vic-]曲妥珠单抗 duocarmazine（SYD985），具有可被溶酶体蛋白酶和膜通透性药物切割的连接子，通过旁观者效应消除邻近抗原阴性的细胞。许多抗肿瘤疗法，如 DNA 损伤剂或 CDK4/6 抑制剂，可诱导衰老，这是一种细胞周期停滞稳定的细胞状态。细胞衰老的另一个标志是溶酶体腔室的扩大。鉴于溶酶体与 ADC 作用机制的相关性，我们假设诱导衰老的疗法将增强 HER2 靶向 ADC 的疗效。用 DNA 损伤剂阿霉素和 CDK4/6 抑制剂处理可诱导几种乳腺癌细胞系中溶酶体增大和衰老。虽然衰老诱导药物不会增加 ADC 对靶细胞的细胞毒性作用，但当将 HER2-阴性细胞与 HER2-低表达细胞共培养时，旁观者效应得到增强。敲低实验表明组织蛋白酶 B 在增强的旁观者效应中的重要性，表明组织蛋白酶 B 介导连接子的切割。在乳腺癌患者来源的异种移植模型中，与单独使用任一药物相比，CDK4/6 抑制剂与 SYD985 的联合治疗显示出改善的抗肿瘤效果。这些数据支持将针对 HER2 的下一代 ADC 与诱导细胞衰老的疗法相结合的策略，用于治疗 HER2 异质性和低表达的肿瘤。
将针对 HER2 阳性乳腺癌的 ADC 与诱导细胞衰老的疗法联合使用，可能通过促进针对抗原阴性肿瘤细胞的旁观者效应，提高其治疗效果。
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