BRAF是可以受到治疗靶向作用的原癌基因典型代表，采用RAF和MEK抑制剂治疗BRAFV600E黑素瘤能够导致肿瘤迅速退化。然而，药物引起的重构会产生一种适应药物状态，据认为与获得性耐药和疾病复发有关。在本文中，我们使用基于能量的常微分方程（ODE）建模及蛋白质组、转录组和成像数据相结合的方法研究BRAFV600E黑素瘤细胞中适应性重构机制。我们开发了一种因果追踪ODE模型的方法，并确定了两个平行MAPK反应通路，由于蛋白聚合和药物结合的差异，这些通路对RAF和MEK抑制剂具有不同的敏感性。我们描述了这些通路以及即时-早期信号和转录反馈之间的时间尺度分离如何创造出一种状态，在这种状态下，RAS调节的MAPK通路可以在完全抑制BRAFV600E驱动的通路下被生长因子激活。预计本文方法的进一步发展将产生一种关于黑素瘤适应性耐药的统一模型。© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

BRAF is prototypical of oncogenes that can be targeted therapeutically and the treatment of BRAFV600E melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring generates a drug adapted state thought to be involved in acquired resistance and disease recurrence. In this article, we study mechanisms of adaptive rewiring in BRAFV600E melanoma cells using an energy-based implementation of ordinary differential equation (ODE) modeling in combination with proteomic, transcriptomic and imaging data. We develop a method for causal tracing of ODE models and identify two parallel MAPK reaction channels that are differentially sensitive to RAF and MEK inhibitors due to differences in protein oligomerization and drug binding. We describe how these channels, and timescale separation between immediate-early signaling and transcriptional feedback, create a state in which the RAS-regulated MAPK channel can be activated by growth factors under conditions in which the BRAFV600E -driven channel is fully inhibited. Further development of the approaches in this article is expected to yield a unified model of adaptive drug resistance in melanoma.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.