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

  • NPJ Precis Oncol. 2026 Apr 2;10(1):142. doi: 10.1038/s41698-026-01385-2.
Masaki Ishida  1 ,  Tadaaki Yamada  2 ,  Yuki Katayama  1 ,  Hayato Kawachi  1 ,  Ryo Sawada  1 ,  Ryota Nakamura  1 ,  Soichi Hirai  1 ,  Yohei Matsui  1 ,  Kenji Morimoto  1 ,  Keisuke Onoi  1 ,  Aosa Nakamura-Sasada  1 ,  Mano Horinaka  3 ,  Toshiyuki Sakai  3 ,  Tomoki Sakakida  4 ,  Toshifumi Doi  4 ,  Kazuo Yasumoto  5 ,  Yasuhiro Goto  6 ,  Naoki Furuya  7 ,  Hirokazu Taniguchi  8 ,  Hirokazu Ogino  9 ,  Nakano Takayuki  10 ,  Yusuke Chihara  11 ,  Koji Fukuda  12 ,  Hiroaki Taniguchi  12 ,  Hisanori Uehara  13 ,  Seiji Yano  12  14 ,  Shinsaku Tokuda  1 ,  Koichi Takayama  1
Affiliations
  • 1. Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kamigyo-ku, Kyoto, Japan.
  • 2. Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kamigyo-ku, Kyoto, Japan. [email protected].
  • 3. Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kamigyo-ku, Kyoto, Japan.
  • 4. Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • 5. Department of Medical Oncology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
  • 6. Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
  • 7. Department of Respiratory Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
  • 8. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
  • 9. Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
  • 10. Department of Respiratory Medicine, Fukuchiyama City Hospital, Kyoto, Japan.
  • 11. Department of Respiratory Medicine, Uji Tokushukai Medical Center, Uji, Kyoto, Japan.
  • 12. Division of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
  • 13. Department of Diagnostic Pathology, Tokushima University Hospital, Tokushima, Japan.
  • 14. Department of Respiratory medicine, Kanazawa Graduate School of Medical Sciences, Kanazawa, Japan.
PMID: 41927886 DOI: 10.1038/s41698-026-01385-2
Abstract

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.

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