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<p><i>KRAS</i> mutations are significant drivers in various cancers, and existing drug discovery attempts targeting these mutations have largely been unsuccessful, emphasizing the need for more effective therapies. In this study, the screening library, which contains 1,374 chemical compounds, identified nintedanib, a VEGFR inhibitor, as exerting a potent and selective antiproliferative effect against <i>KRAS</i>-mutant cells, surpassing other VEGFR inhibitors. Nintedanib effectively suppressed tumor growth in xenografted mice with <i>KRAS</i> mutations and significantly inhibited phosphorylated VEGFR2 levels and its downstream signaling molecules pAKT and pERK in <i>KRAS</i>-mutant cells, suggesting that VEGFR2 inhibition affects the oncogenic AKT/ERK pathway. Moreover, in VEGFR2-knockout cells, inhibition of SOS1 protein reduced KRAS-GTP activity, which decreased the phosphorylation of ERK, AKT, and DRP1, thereby inducing apoptosis. Remarkably, <i>KRAS</i><sup>G12D</sup> overexpression augmented VEGFR2 expression, establishing a positive feedback loop between <i>KRAS</i> mutations and VEGFR2 signaling within the ERK pathway. Immunohistochemical analyses of pancreatic cancer tissues revealed high VEGFR2 expression in 83% (67/80) of samples, significantly exceeding the levels observed in normal pancreatic tissues. These results underscore VEGFR2 as a promising molecular target and propose a novel therapeutic avenue for <i>KRAS</i>-mutant cancers.</p>

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Nintedanib inhibits the VEGFR–ERK signaling pathway in human KRAS-mutated cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Sivasundaram Karnan,
  • Akinobu Ota,
  • Muhammad Nazmul Hasan,
  • Toshinori Hyodo,
  • Nushrat Jahan,
  • Hideki Murakami,
  • Md Towhid Ahmed Shihan,
  • Ichiro Hanamura,
  • Lam Quang Vu,
  • Miho Riku,
  • Hideaki Ito,
  • Yoshifumi Kaneko,
  • Yinzhi Lin,
  • Md Wahiduzzaman,
  • Md. Lutfur Rahman,
  • Shingo Inaguma,
  • Takuya Matsui,
  • Hiroyuki Konishi,
  • Shinobu Tsuzuki,
  • Yoshitaka Hosokawa

摘要

KRAS mutations are significant drivers in various cancers, and existing drug discovery attempts targeting these mutations have largely been unsuccessful, emphasizing the need for more effective therapies. In this study, the screening library, which contains 1,374 chemical compounds, identified nintedanib, a VEGFR inhibitor, as exerting a potent and selective antiproliferative effect against KRAS-mutant cells, surpassing other VEGFR inhibitors. Nintedanib effectively suppressed tumor growth in xenografted mice with KRAS mutations and significantly inhibited phosphorylated VEGFR2 levels and its downstream signaling molecules pAKT and pERK in KRAS-mutant cells, suggesting that VEGFR2 inhibition affects the oncogenic AKT/ERK pathway. Moreover, in VEGFR2-knockout cells, inhibition of SOS1 protein reduced KRAS-GTP activity, which decreased the phosphorylation of ERK, AKT, and DRP1, thereby inducing apoptosis. Remarkably, KRASG12D overexpression augmented VEGFR2 expression, establishing a positive feedback loop between KRAS mutations and VEGFR2 signaling within the ERK pathway. Immunohistochemical analyses of pancreatic cancer tissues revealed high VEGFR2 expression in 83% (67/80) of samples, significantly exceeding the levels observed in normal pancreatic tissues. These results underscore VEGFR2 as a promising molecular target and propose a novel therapeutic avenue for KRAS-mutant cancers.