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<p>Mutations in K/H/N-RAS occur in approximately 30% of human cancers, yet most RAS mutants remain undruggable in clinical settings. Here, we describe a protein-based pan-RAS inhibitor, RRSP-RBD, that combines a RAS/Rap1A-specific endopeptidase (RRSP) with a RAS-binding domain (RBD). This engineered fusion protein localizes to RAS on the plasma membrane, where it cleaves RAS, disrupts RAS-effector interactions, and effectively inhibits downstream RAS signaling. To achieve intracellular delivery of RRSP-RBD in vivo, we engineer two cell-permeable variants. The diphtheria toxin-based version (RRSP-RBD-DTB) demonstrates femtomolar anti-tumor potency and induces tumor regression in a xenograft mouse model. The cell-permeable peptide-based version (RRSP-RBD-TAT) exhibits robust anti-tumor activity in syngeneic models without inducing irreversible toxicity in normal tissues. Interestingly, anti-tumor efficacy of RRSP-RBD-TAT critically depends on the tumor microenvironment, requiring infiltration by IFNγ<sup>+</sup> CD8<sup>+</sup> T cells to mediate tumor regression. Pharmacokinetic and toxicity evaluations indicate that RRSP-RBD is tolerated under the conditions tested and support further investigation as a protein-based pan-RAS inhibitor (all mouse studies were performed in female mice).</p>

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Protein-based pan-RAS inhibitor induces tumor regression in female mice via IFNγ and CD8+ T cell-dependent tumor necrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Teiko Komori Nomura,
  • Kazuki Heishima,
  • Hidefumi Mukai,
  • Kosuke Arai,
  • Abdelazim Elsayed Elhelaly,
  • Hirobumi Fuchigami,
  • Shota Warashina,
  • Tsuyoshi Tahara,
  • Fuminori Hyodo,
  • Masayuki Matsuo,
  • Masahiro Yasunaga,
  • Kazunori Aoki,
  • Ryo Honda

摘要

Mutations in K/H/N-RAS occur in approximately 30% of human cancers, yet most RAS mutants remain undruggable in clinical settings. Here, we describe a protein-based pan-RAS inhibitor, RRSP-RBD, that combines a RAS/Rap1A-specific endopeptidase (RRSP) with a RAS-binding domain (RBD). This engineered fusion protein localizes to RAS on the plasma membrane, where it cleaves RAS, disrupts RAS-effector interactions, and effectively inhibits downstream RAS signaling. To achieve intracellular delivery of RRSP-RBD in vivo, we engineer two cell-permeable variants. The diphtheria toxin-based version (RRSP-RBD-DTB) demonstrates femtomolar anti-tumor potency and induces tumor regression in a xenograft mouse model. The cell-permeable peptide-based version (RRSP-RBD-TAT) exhibits robust anti-tumor activity in syngeneic models without inducing irreversible toxicity in normal tissues. Interestingly, anti-tumor efficacy of RRSP-RBD-TAT critically depends on the tumor microenvironment, requiring infiltration by IFNγ+ CD8+ T cells to mediate tumor regression. Pharmacokinetic and toxicity evaluations indicate that RRSP-RBD is tolerated under the conditions tested and support further investigation as a protein-based pan-RAS inhibitor (all mouse studies were performed in female mice).