Drug Resistance and Persistent Signalling States: A Compartmental Redistribution Framework

Drug resistance and persistent signalling states are frequently attributed to receptor mutation, transcriptional rewiring, or pathway redundancy. However, accumulating evidence across receptor families indicates that functional output is strongly shaped by subcellular localisation and compartment dominance. This manuscript introduces a compartmental redistribution framework, termed Subcellular Target Relocation (STR), in which signalling behaviour emerges from state-conditioned shifts in receptor distribution rather than changes in receptor identity or abundance. STR formalises receptor configuration as a probabilistic weighting across intracellular compartments Cᵢ conditioned on system state S(t). Regulatory variables including kinase tone, membrane lipid organisation, inflammatory signalling, energetic stress, and chronic agonism bias trafficking probabilities and alter compartment dominance. Redistribution can therefore modify signalling availability and pharmacological responsiveness without requiring genetic alteration. Mechanistic examples are drawn from GPCR internalisation and routing, lipid-domain regulation of receptor diffusion and clustering, mitochondrial-associated receptor pools, and AMPA receptor synaptic scaling. The framework also provides a structural explanation for hysteresis, in which prior redistribution constrains recovery trajectories through layered trafficking commitments and energetic limitations. This model reframes drug resistance and signalling persistence as topology-dependent phenomena arising from compartment reweighting within dynamic cellular systems.