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<p>Oncogene-directed tyrosine kinase inhibitors (TKIs) have transformed the treatment of molecularly defined cancers; however, durable responses are frequently undermined by therapy-induced adaptive resistance. Beyond secondary kinase mutations, accumulating evidence suggests that stress-responsive, non-genetic survival pathways play a central role in attenuating TKI efficacy across oncogenic contexts. The TWEAK/FN14 signaling axis has been implicated in stress-induced, NF-κB–mediated survival signaling, yet its role as a convergent mediator of adaptive resistance to oncogene-targeted therapies remains incompletely defined. We performed a structure-guided virtual screen of approximately 1.3 million compounds evaluated across multiple FN14 binding interface models, yielding ~3.9 million docking simulations, to identify small molecules capable of disrupting TWEAK/FN14 signaling. Lead candidates were validated using TWEAK/FN14 and TNFα-driven NF-κB reporter assays with cytotoxicity controls. Combination studies were conducted across a broad panel of Ba/F3 models expressing oncogenic drivers—including RET, ALK, ROS1, NTRK, EGFR exon 20 insertion, BRAF V600E, and KRAS G12C—each paired with matched TKIs and resistance mutations. Drug interactions were quantified using Bliss independence and Loewe additivity models. <i>In vivo</i> efficacy was evaluated in a Ba/F3 KIF5B–RET G810R xenograft model. Cabozantinib, zanzalintinib, and selected screening-derived compounds inhibited TWEAK/FN14-induced NF-κB signaling at nanomolar concentrations, with minimal effects on TNFα-mediated signaling and limited intrinsic cytotoxicity. TWEAK/FN14 inhibition consistently enhanced the anti-tumor activity of oncogene-matched TKIs across all seven oncogenic driver classes, including models harboring clinically relevant resistance mutations. Synergistic interactions were observed across multiple TKI combinations, demonstrating greater-than-additive suppression of oncogene-driven cell survival. In vivo, combined selpercatinib and cabozantinib treatment resulted in significantly greater tumor growth inhibition than either monotherapy in a RET G810R resistance model, without evidence of toxicity. These findings are consistent with TWEAK/FN14 signaling functioning as a broadly exploitable adaptive resistance pathway across diverse oncogenic contexts. Pharmacologic disruption of this pathway, including through repurposing of clinically advanced agents such as cabozantinib, represents a rational and testable strategy to enhance the efficacy of oncogene-directed TKIs; genetic validation of the FN14-specific mechanism is warranted for future investigation.</p>

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TWEAK/FN14 inhibition synergizes with oncogene-directed tyrosine kinase inhibitors to overcome resistance across multiple driver contexts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Glen J. Weiss,
  • Joseph C. Loftus,
  • David W. Mallery,
  • Nhan L. Tran

摘要

Oncogene-directed tyrosine kinase inhibitors (TKIs) have transformed the treatment of molecularly defined cancers; however, durable responses are frequently undermined by therapy-induced adaptive resistance. Beyond secondary kinase mutations, accumulating evidence suggests that stress-responsive, non-genetic survival pathways play a central role in attenuating TKI efficacy across oncogenic contexts. The TWEAK/FN14 signaling axis has been implicated in stress-induced, NF-κB–mediated survival signaling, yet its role as a convergent mediator of adaptive resistance to oncogene-targeted therapies remains incompletely defined. We performed a structure-guided virtual screen of approximately 1.3 million compounds evaluated across multiple FN14 binding interface models, yielding ~3.9 million docking simulations, to identify small molecules capable of disrupting TWEAK/FN14 signaling. Lead candidates were validated using TWEAK/FN14 and TNFα-driven NF-κB reporter assays with cytotoxicity controls. Combination studies were conducted across a broad panel of Ba/F3 models expressing oncogenic drivers—including RET, ALK, ROS1, NTRK, EGFR exon 20 insertion, BRAF V600E, and KRAS G12C—each paired with matched TKIs and resistance mutations. Drug interactions were quantified using Bliss independence and Loewe additivity models. In vivo efficacy was evaluated in a Ba/F3 KIF5B–RET G810R xenograft model. Cabozantinib, zanzalintinib, and selected screening-derived compounds inhibited TWEAK/FN14-induced NF-κB signaling at nanomolar concentrations, with minimal effects on TNFα-mediated signaling and limited intrinsic cytotoxicity. TWEAK/FN14 inhibition consistently enhanced the anti-tumor activity of oncogene-matched TKIs across all seven oncogenic driver classes, including models harboring clinically relevant resistance mutations. Synergistic interactions were observed across multiple TKI combinations, demonstrating greater-than-additive suppression of oncogene-driven cell survival. In vivo, combined selpercatinib and cabozantinib treatment resulted in significantly greater tumor growth inhibition than either monotherapy in a RET G810R resistance model, without evidence of toxicity. These findings are consistent with TWEAK/FN14 signaling functioning as a broadly exploitable adaptive resistance pathway across diverse oncogenic contexts. Pharmacologic disruption of this pathway, including through repurposing of clinically advanced agents such as cabozantinib, represents a rational and testable strategy to enhance the efficacy of oncogene-directed TKIs; genetic validation of the FN14-specific mechanism is warranted for future investigation.