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<p>RAF kinases are key effectors in the RAS–RAF–MEK–ERK signaling pathway, making them important targets for the development of cancer therapeutics. Here we investigate the variable potency of DFG-out-stabilizing RAF inhibitors in mutant KRAS-expressing cell lines. We demonstrate that inhibitor potency correlates with basal RAF activity, with more active RAF being more sensitive to inhibition. We further show that DFG-out-stabilizing inhibitors disrupt high-affinity RAF–MEK interactions, promoting the formation of inhibited RAF dimers. Furthermore, we identify cobimetinib as an MEK inhibitor that uniquely sensitizes RAF kinases to DFG-out-stabilizing inhibitors by disrupting autoinhibited RAF–MEK complexes. Building on this insight, we developed cobimetinib analogs with enhanced sensitization properties. Together, our findings provide a mechanistic framework for understanding the cellular determinants of DFG-out-stabilizing inhibitor sensitivity and offer strategies for optimizing synergistic RAF–MEK inhibitor combinations.</p><p></p>

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MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月12日

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  • Ethan G. Stoddard,
  • B. Gayani K. Perera,
  • Linglan Fang,
  • Daniel S. Brush,
  • Yuhao Zhong,
  • Zachary E. Potter,
  • Jessica J. Simon,
  • Martin Golkowski,
  • Dustin J. Maly

摘要

RAF kinases are key effectors in the RAS–RAF–MEK–ERK signaling pathway, making them important targets for the development of cancer therapeutics. Here we investigate the variable potency of DFG-out-stabilizing RAF inhibitors in mutant KRAS-expressing cell lines. We demonstrate that inhibitor potency correlates with basal RAF activity, with more active RAF being more sensitive to inhibition. We further show that DFG-out-stabilizing inhibitors disrupt high-affinity RAF–MEK interactions, promoting the formation of inhibited RAF dimers. Furthermore, we identify cobimetinib as an MEK inhibitor that uniquely sensitizes RAF kinases to DFG-out-stabilizing inhibitors by disrupting autoinhibited RAF–MEK complexes. Building on this insight, we developed cobimetinib analogs with enhanced sensitization properties. Together, our findings provide a mechanistic framework for understanding the cellular determinants of DFG-out-stabilizing inhibitor sensitivity and offer strategies for optimizing synergistic RAF–MEK inhibitor combinations.