Department of Mechanical and Industrial Engineering, Norwegian University of Science and Technology, Trondheim, Norway.
Institute of Physics of the University of São Paulo, Department of General Physics, São Paulo, Brazil.
PLoS Comput Biol. 2024 Nov 7;20(11):e1012570. doi: 10.1371/journal.pcbi.1012570. eCollection 2024 Nov.
Resistance to therapy is a major clinical obstacle to treatment of cancer and communicable diseases. Drug selection in treatment of patients where the disease is showing resistance to therapy is often guided by IC50 or fold-IC50 values. In this work, through a model of the treatment of chronic myeloid leukaemia (CML), we contest using fold-IC50 values as a guide for treatment selection. CML is a blood cancer that is treated with Abl1 inhibitors, and is often seen as a model for targeted therapy and drug resistance. Resistance to the first-line treatment occurs in approximately one in four patients. The most common cause of resistance is mutations in the Abl1 enzyme. Different mutant Abl1 enzymes show resistance to different Abl1 inhibitors and the mechanisms that lead to resistance for various mutation and inhibitor combinations are not fully known, making the selection of Abl1 inhibitors for treatment a difficult task. We developed a model based on information of catalysis, inhibition and pharmacokinetics, and applied it to study the effect of three Abl1 inhibitors on mutants of the Abl1 enzyme. From this model, we show that the relative decrease of product formation rate (defined in this work as "inhibitory reduction prowess") is a better indicator of resistance than an examination of the size of the product formation rate or fold-IC50 values for the mutant. We also examine current ideas and practices that guide treatment choice and suggest a new parameter for selecting treatments that could increase the efficacy and thus have a positive impact on patient outcomes.
耐药性是癌症和传染病治疗的主要临床障碍。在治疗疾病对治疗产生耐药性的患者时，药物选择通常受 IC50 或 fold-IC50 值的指导。在这项工作中，我们通过慢性髓性白血病 (CML) 的治疗模型，对使用 fold-IC50 值作为治疗选择指南提出质疑。CML 是一种血液癌，用 Abl1 抑制剂治疗，通常被视为靶向治疗和耐药性的模型。大约四分之一的患者会对一线治疗产生耐药性。耐药性最常见的原因是 Abl1 酶的突变。不同的突变 Abl1 酶对不同的 Abl1 抑制剂表现出耐药性，并且导致各种突变和抑制剂组合产生耐药性的机制尚未完全清楚，因此选择 Abl1 抑制剂进行治疗是一项艰巨的任务。我们开发了一个基于催化、抑制和药代动力学信息的模型，并将其应用于研究三种 Abl1 抑制剂对 Abl1 酶突变体的影响。从这个模型中，我们表明产物形成速率的相对降低（在本工作中定义为“抑制还原能力”）比检查产物形成速率或突变体的 fold-IC50 值更能指示耐药性。我们还检查了指导治疗选择的当前理念和实践，并提出了一个新的参数来选择治疗方法，这可能会提高疗效，从而对患者的预后产生积极影响。
