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<p>Human epidermal growth factor receptor 2 (HER2)-tyrosine kinase inhibitors (TKIs) are being developed for the treatment of patients with HER2-aberrant lung and gastric cancers. However, achieving complete tumor remission remains challenging. Here, we investigated the molecular mechanisms underlying adaptive resistance to HER2-TKIs in HER2-aberrant tumor cells in order to devise strategies to prevent the emergence of drug-tolerant cells. Our findings showed that the AXL receptor was activated by HER2-TKIs and maintained cell survival by interacting with epidermal growth factor receptor, HER2, and HER3. This process, mediated by the SHC1BP–SHC1 axis, contributed to adaptive resistance to HER2-TKIs in a subset of HER2-aberrant lung and gastric cancers. AXL inhibition significantly delayed tumor regrowth of AXL-overexpressing cells by enhancing HER2-TKI-induced apoptosis in xenograft models. These results suggest that patients with HER2-aberrant lung and gastric cancers exhibiting high AXL expression may benefit from an initial combination therapy with an AXL inhibitor.</p>

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AXL–SHC1 signaling axis mediates adaptive resistance to HER2-targeted tyrosine kinase inhibitors in HER2-aberrant lung and gastric cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Masaki Ishida,
  • Tadaaki Yamada,
  • Yuki Katayama,
  • Hayato Kawachi,
  • Ryo Sawada,
  • Ryota Nakamura,
  • Soichi Hirai,
  • Yohei Matsui,
  • Kenji Morimoto,
  • Keisuke Onoi,
  • Aosa Nakamura-Sasada,
  • Mano Horinaka,
  • Toshiyuki Sakai,
  • Tomoki Sakakida,
  • Toshifumi Doi,
  • Kazuo Yasumoto,
  • Yasuhiro Goto,
  • Naoki Furuya,
  • Hirokazu Taniguchi,
  • Hirokazu Ogino,
  • Nakano Takayuki,
  • Yusuke Chihara,
  • Koji Fukuda,
  • Hiroaki Taniguchi,
  • Hisanori Uehara,
  • Seiji Yano,
  • Shinsaku Tokuda,
  • Koichi Takayama

摘要

Human epidermal growth factor receptor 2 (HER2)-tyrosine kinase inhibitors (TKIs) are being developed for the treatment of patients with HER2-aberrant lung and gastric cancers. However, achieving complete tumor remission remains challenging. Here, we investigated the molecular mechanisms underlying adaptive resistance to HER2-TKIs in HER2-aberrant tumor cells in order to devise strategies to prevent the emergence of drug-tolerant cells. Our findings showed that the AXL receptor was activated by HER2-TKIs and maintained cell survival by interacting with epidermal growth factor receptor, HER2, and HER3. This process, mediated by the SHC1BP–SHC1 axis, contributed to adaptive resistance to HER2-TKIs in a subset of HER2-aberrant lung and gastric cancers. AXL inhibition significantly delayed tumor regrowth of AXL-overexpressing cells by enhancing HER2-TKI-induced apoptosis in xenograft models. These results suggest that patients with HER2-aberrant lung and gastric cancers exhibiting high AXL expression may benefit from an initial combination therapy with an AXL inhibitor.