Hsp70‐Bim incoherent feedforward loop contributes to cell‐fate heterogeneity and fractional killing

Abstract

Background and PurposeAlthough 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 ApproachMathematical 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 ResultsThe 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 ImplicationsHsp70‐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.