Background and purpose: Although chemotherapeutics or molecular targeted drugs often elicit profound initial responses, fractional killing capable of driving acquired resistance can persist. Identifying stress-induced negative feedback or an incoherent feedforward loop (IFFL), which may contribute to fractional killing, is urgently needed.
Experimental approach: Mathematical modelling was used to identify how and to what extent a recently reported Hsp70-Bim protein-protein interaction (PPI) contributes to the adaptation of the Bcl-2 network. Experimental validation was made by using a specific inhibitor of Hsp70-Bim PPI, S1g-2, as chemical tool. Bifurcation analysis and stochastic simulation were used for the theoretical study of the impact of Hsp70-Bim PPI on cell-fate heterogeneity and factional killing.
Key results: The Hsp70-Bim-AKT circuit forms an IFFL that greatly contributes to the adaptation of the Bcl-2-regulated apoptosis network, thus leading to fractional killing. This adaptive programme enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario.
Conclusion and implications: Hsp70-Bim IFFL serves as a molecular pathway induced by DNA damaging drugs or tyrosine kinase inhibitors that enabled fractional killing, whereby acquired resistance emerges. A synergistic strategy is unveiled for overcoming fractional killing by suppressing Hsp70-Bim PPI.
Keywords: Hsp70-Bim; apoptosis; cell-fate heterogeneity; fractional killing; incoherent feedforward loop.
© 2023 British Pharmacological Society.