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

Abstract

BRAFV600E is prototypical of oncogenic mutations that can be targeted therapeutically and treatment of BRAF-mutant melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring causes BRAFV600E melanoma cells to rapidly acquire a drug-adapted state. In patients this is thought to promote acquisition or selection for resistance mutations and disease recurrence. In this paper we use an energy-based implementation of ordinary differential equations in combination with proteomic, transcriptomic and imaging data from melanoma cells, to model the precise mechanisms responsible for adaptive rewiring. We demonstrate the presence of two parallel MAPK (RAF-MEK-ERK kinase) reaction channels in BRAFV600E melanoma cells that are differentially sensitive to RAF and MEK inhibitors. This arises from differences in protein oligomerization and allosteric regulation induced by oncogenic mutations and drug binding. As a result, the RAS-regulated MAPK channel can be active under conditions in which the BRAFV600E-driven channel is fully inhibited. Causal tracing demonstrates that this provides a sufficient quantitative explanation for initial and acquired responses to multiple different RAF and MEK inhibitors individually and in combination.

Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation

“…Although inhibitor-modulated CA has been recognized as a possible contributor to the entire PA phenomenon ( Heidorn et al, 2010 ; Jin et al, 2017 ), it has been underappreciated as a mechanism capable of driving PA. Supporting this assertion is that CA has neither been discussed as a motivation for the development of third-generation RAF inhibitors ( Nakamura et al, 2013 ; Peng et al, 2015 ; Zhang et al, 2015 ) nor has it been included in recent mathematical analyses of PA and of RAF signaling ( Fröhlich et al, 2022 ; Kholodenko, 2015 ; Rukhlenko et al, 2018 ; Varga et al, 2017 ). This is notable as both drug development and mathematical analyses pay considerable attention to conformations within the kinase domain (i.e., whether the alpha-C helix and DFG motif are in the ‘in’ or ‘out’ conformations) ( Kholodenko, 2015 ; Nakamura et al, 2013 ; Peng et al, 2015 ; Rukhlenko et al, 2018 ; Zhang et al, 2015 ).…”

Fides: Reliable trust-region optimization for parameter estimation of ordinary differential equation models

“…Until then, the availability of multiple Hessian approximation schemes and trust-region sub-problem solvers in fides will be of general utility with a range of models. We have used it ourselves with large ODE-based models that are on the limit of what can be considered practically [56]. Similarly, fides will be a sound foundation for the development of new and better optimization methods.…”