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

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

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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