Abstract 1721: AXL signaling promotes adaptive resistance to HER2 tyrosine kinase inhibitors in HER2 aberrant tumor cells

Abstract Introduction: Human epidermal growth factor receptor 2 (HER2) is an oncogene target in various cancers, including lung, stomach, and breast cancers. Several HER2-tyrosine kinase inhibitors (TKIs) have been developed for clinical use in patients with tumors exhibiting HER2 aberrations. However, achieving complete tumor remission remains challenging. Therefore, identifying optimal combined therapeutic approaches with HER2-TKIs is crucial for improving clinical outcomes. This study focuses on elucidating the adaptive resistance mechanisms to HER2-TKIs and the therapeutic strategies needed to overcome this resistance. Methods: We conducted in vitro and in vivo experiments using HER2-aberrant tumor cell lines to evaluate the adaptive responses to HER2-TKIs. The involvement of AXL signaling was examined using MTT assays, western blotting, qPCR, and flow cytometer. Results: We showed that adaptive resistance to HER2-TKIs in HER2-aberrant tumors is mediated by AXL signaling, activation of which is induced by its ligand GAS6 production. Inhibition of AXL reduced the viability of HER2-aberrant tumor cells that overexpress AXL by enhancing apoptosis and cell cycle arrest induced by HER2 inhibition. This process contributed to adaptive resistance to HER2-TKIs in HER2-aberrant cancers through the Shc1BP-Shc1 axis, one of the adaptor proteins. HER2-TKIs induced the dissociation of ShcBP1 from Shc1, promoted the binding of Shc1 to AXL, and triggered the translocation of ShcBP1 to the nucleus, which is associated with the cell cycle. In xenograft models of AXL-overexpressing HER2-aberrant tumors treated with HER2-TKIs, initial combination therapy with an AXL inhibitor significantly reduced tumor size and delayed tumor regrowth compared to HER2-TKI monotherapy. Conclusion: These findings highlight the critical role of the GAS6-AXL signaling axis in intrinsic resistance to HER2-TKIs and the potential benefits of its inhibition in overcoming this resistance. Citation Format: Masaki Ishida, Tadaaki Yamada, Yuki Katayama, Kazuo Yasumoto, Koichi Takayama. AXL signaling promotes adaptive resistance to HER2 tyrosine kinase inhibitors in HER2 aberrant tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1721.