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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Mathematical Biology

Background:

  • RAF kinase inhibitors can paradoxically increase RAF signaling (PA).
  • Conformational autoinhibition (CA) disruption by RAF inhibitors contributes to PA.
  • 14-3-3 proteins are known regulators of RAF CA and dimerization.

Purpose of the Study:

  • To mathematically model and experimentally investigate the role of 14-3-3 proteins in RAF inhibitor PA.
  • To derive analytical expressions for RAF signal regulation modulated by 14-3-3 proteins.

Main Methods:

  • Extended a mathematical model of RAF signaling to incorporate 14-3-3 protein functions.
  • Derived analytical expressions for RAF signal regulation.
  • Performed experimental validation using forced 14-3-3 expression and evolved resistance assays.

Main Results:

  • Mathematical model predicts 14-3-3 proteins can potentiate PA by stabilizing autoinhibited RAF.
  • Model suggests 14-3-3 proteins can reduce PA by stabilizing active RAF dimers.
  • Experimental data confirmed that increased 14-3-3 expression amplifies PA.
  • Increased 14-3-3 expression may contribute to resistance against RAF inhibitors.

Conclusions:

  • 14-3-3 proteins play a significant role in modulating RAF inhibitor-induced paradoxical activation.
  • 14-3-3 proteins can potentially induce PA even for inhibitors with minimal PA.
  • Findings suggest therapeutic targeting of 14-3-3 interactions may be a strategy for overcoming RAF inhibitor resistance.