Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance

BRAF is prototypical of oncogenes that can be targeted therapeutically and the treatment of BRAF V600E 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 BRAF V600E 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 BRAF V600E ‐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. Synopsis An energy‐based, mechanistic model of MAPK signaling is developed to describe the network rewiring responsible for adaptive (non‐genetic) and genetic resistance to RAF and MEK inhibitors in BRAF‐mutant cancers. A thermodynamic framework enables a structure‐based description of allosteric interactions in the EGFR and MAPK pathways. Causal decomposition of the efficacy of targeted drugs elucidates the rewiring of MAPK channels. Model‐based extrapolation is performed from type I½ RAF inhibitors to type II RAF inhibitors. A unified mechanistic explanation for adaptive and genetic resistance across BRAF‐cancers is provided. Graphical Abstract An energy‐based, mechanistic model of MAPK signaling is developed to describe the network rewiring responsible for adaptive (non‐genetic) and genetic resistance to RAF and MEK inhibitors in BRAF‐mutant cancers.