Kinetic Remodeling in Durable Response and Resistance

Durable therapeutic response depends not only on suppressing a disease-associated pathway, but also on changing the cellular dynamics that permit pathological or drug-tolerant states to persist and re-emerge. We distinguish transient activity modulation from kinetic remodeling, defined as a change in the drift, noise, flux, stability or transition structure governing cell-state accessibility. Using MAPK signaling as a model system, we organize remodeling into five idealized modes and link each to measurable signatures, including altered occupancy, switching, hysteresis and post-withdrawal recovery. This framework provides an experimental basis for identifying interventions that produce durable state control rather than temporary pathway inhibition.