Franciosa Giulia, Smits Jos G A, Minuzzo Sonia, Martinez-Val Ana, Indraccolo Stefano, Olsen Jesper V
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Department of Molecular Developmental Biology, Radboud University, Nijmegen, Netherlands.
Nat Commun. 2021 May 4;12(1):2507. doi: 10.1038/s41467-021-22787-9.
Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.
Notch1是T细胞急性淋巴细胞白血病（T-ALL）中一种关键的致癌驱动因子，使其成为一个有吸引力的治疗靶点。然而，由于耐药性的产生，使用γ-分泌酶抑制剂（GSIs）（一种阻断Notch切割及后续激活的小分子）进行靶向治疗的成功率有限，从而限制了其临床疗效。在此，我们使用耐药性的互补模型，包括T-ALL患者来源的异种移植（PDX）模型，通过基于定量质谱的磷酸化蛋白质组学系统地比较GSI耐药和敏感细胞状态。我们的数据集揭示了GSI耐药的常见机制，包括涉及蛋白激酶Cδ的独特激酶特征。我们证明蛋白激酶C抑制剂索拉非尼在PDX模型中增强了GSI的抗白血病活性，并在体外完全消除了获得性GSI耐药的发展。总体而言，我们强调了蛋白质组学在剖析细胞信号变化和识别癌症中可药物化途径方面的潜力。
