Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 19, Issue 2, Pages -Publisher
WILEY
DOI: 10.15252/msb.202210988
Keywords
allosteric interactions; drug resistance; kinetic modeling; MAPK pathway; rewiring
Categories
Ask authors/readers for more resources
In this article, the mechanisms of adaptive rewiring in BRAF(V600E) melanoma cells were studied using an energy-based implementation of ordinary differential equation (ODE) modeling in combination with proteomic, transcriptomic and imaging data. Two parallel MAPK reaction channels were identified, which showed differential sensitivity to RAF and MEK inhibitors due to differences in protein oligomerization and drug binding. The study also revealed the time scale separation between immediate-early signaling and transcriptional feedback, creating a state in which the RAS-regulated MAPK channel can be activated by growth factors under conditions of fully inhibited BRAF(V600E)-driven channel. Further development of the approaches in this article is expected to yield a unified model of adaptive drug resistance in melanoma.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available