Abstract 846: Co-targeting of Axl and MerTK improves radiation response in HNSCC

Axl and MerTK are members of the TAM family (Tyro, Axl and MerTK) of receptor tyrosine kinases and have been reported to be altered in several types of cancer including Head and Neck Squamous Carcinoma (HNSCC). It is well known that aberrant expression or activity of Axl is associated with resistance to various therapies. Therefore, the translational potential of targeting AXL in HNSCC is worthy, however poorly defined. We recently identified an adaptive feedback mechanism of resistance to AXL-targeting agents mediated by upregulation of MerTK that reveals a direct role for MerTK in resistance to Axl inhibition. In this study, we investigated potential radiosensitization by dual targeting of Axl and MerTK in combination with radiation in human HNSCC cell lines and xenografts (SCC47 and TU138). Immunoblot analysis demonstrated that endogenous levels of Axl or MerTK expression were distinct between these two cell lines. SCC47 cells expressed higher endogenous levels of Axl compared to Tu138. Tu138 expressed higher levels of MerTK compared to SCC47 cells. Radiation induced Axl phosphorylation in SCC47 cells but not in Tu138 cells in vitro. Next, inhibitors of Axl (R428) and/or MerTK (UNC2025) were utilized in combination with single dose radiation in vitro. Clonogenic assays showed that the Axl inhibitor alone acted as a potent radiosensitizer in SCC47 cells. To better define Axl9s role in radiation response in HNSCC, we developed HN30-Vector and HN30-Axl stable cells and exposed them to radiation. Phosphorylation of Axl was increased 1 hour post-radiation in Axl overexpressed HN30 compared to parental HN30-Vector which expresses low endogenous levels of Axl. We also found that the HN30-Axl cell line was associated with radioresistance by clonogenic assays. Tumor xenograft studies demonstrated that the combination of R428 and UNC2025 inhibitors improved the efficacy of radiation in Tu138 but not in SCC47. Interestingly, radiation therapy alone was more effective in SCC47 tumors than TU138 tumors. These results reveal that the co-targeting of Axl and MerTK enhanced tumor growth delay in TU138 xenograft mouse models in vivo. Mechanisms of radiosensitization are currently under investigation. Citation Format: Mahyar Abbariki, Mahmoud Toulany, Mari Iida, Alecia Morgan, Kwang Nickel, Nellie McDaniel, Grace Kang, Chunrong Li, Paul Harari, Deric Wheeler. Co-targeting of Axl and MerTK improves radiation response in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 846.