AXL–SHC1 signaling axis mediates adaptive resistance to HER2-targeted tyrosine kinase inhibitors in HER2-aberrant lung and gastric cancers
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.
Authors
- Soichi Hirai (ORCID: https://orcid.org/0000-0002-2537-6499)
- Yasuhiro Gotô (ORCID: https://orcid.org/0000-0003-2235-8567)
- Keisuke Onoi
- Mano Horinaka (ORCID: https://orcid.org/0000-0001-8168-1802)
- Yusuke Chihara (ORCID: https://orcid.org/0000-0002-7533-844X)
- Ryo Sawada
- Koichi Takayama
- Hisanori Uehara (ORCID: https://orcid.org/0000-0003-1709-1386)
- Yohei Matsui (ORCID: https://orcid.org/0000-0001-7850-5330)
- Tomoki Sakakida (ORCID: https://orcid.org/0000-0003-1913-7923)
- Hayato Kawachi (ORCID: https://orcid.org/0000-0002-1673-2260)
- Naoki Furuya (ORCID: https://orcid.org/0000-0001-7162-5946)
- Shinsaku Tokuda (ORCID: https://orcid.org/0000-0002-3726-7775)
- Kenji Morimoto (ORCID: https://orcid.org/0000-0003-3394-1838)
- Toshifumi Doi (ORCID: https://orcid.org/0000-0002-4305-8937)
- Kazuo Yasumoto (ORCID: https://orcid.org/0000-0002-7890-4929)
- Aosa Nakamura-Sasada
- Nakano Takayuki
- Seiji Yano
- Hirokazu Ogino
- Koji Fukuda
- Toshiyuki Sakai
- Masaki Ishida
- Hirokazu Taniguchi
- Ryota Nakamura
- Hiroaki Taniguchi
- Yuki Katayama
- Tadaaki Yamada
Institutions
- Kanazawa University (JP)
- Fujita Health University (JP)
- St. Marianna University School of Medicine (JP)
- Kanazawa Medical University (JP)
- Kyoto Prefectural University of Medicine (JP)
- Kanazawa Medical Center (JP)
- Fukuoka Tokushukai Hospital (JP)
- Fukuyama City Hospital (JP)
- Tokushima University Hospital (JP)
- Nagasaki University (JP)
- Tokushima University (JP)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2026-04-02
- DOI
- https://doi.org/10.1038/s41698-026-01385-2
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Research Institute
- Cancer Research Institute, Kanazawa University
- Kanazawa University
- Princess Takamatsu Cancer Research Fund
- Japan Society for the Promotion of Science