Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Nat Commun. 2022 Feb 23;13(1):1009. doi: 10.1038/s41467-022-28515-1.
The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer.
免疫调节药物（IMiDs）来那度胺和泊马度胺是多发性骨髓瘤的高效治疗药物。然而，几乎所有患者最终都会因获得性耐药而复发，而耐药相关的遗传改变仅在少数情况下被发现。为了确定耐药的非遗传机制，我们在这里对来自多发性骨髓瘤患者的五对预处理和复发样本进行了基于串联质量标签（TMT）的整合全局定量蛋白质组学和磷酸化蛋白质组学分析以及 RNA 测序。这些分析揭示了一个由 CDK6 控制的蛋白耐药特征，其中包括骨髓瘤高危因素如 TRIP13 和 RRM1。在多发性骨髓瘤细胞系中过表达 CDK6 会降低对 IMiDs 的敏感性，而 palbociclib 抑制 CDK6 或 PROTACs（靶向蛋白水解嵌合体）降解 CDK6 在体外和体内与 IMiDs 具有高度协同作用。这项工作确定了 CDK6 的上调是 IMiD 耐药多发性骨髓瘤的一个可治疗靶点，并强调了蛋白质组学研究在揭示癌症中非遗传耐药机制中的应用。
