AXL inhibition improves the therapeutic efficacy of trastuzumab in high-risk endometrial cancer

Objective: Improved treatment options for HER2-expressing tumors are needed, particularly receptor targeted therapies. The receptor tyrosine kinase AXL, which is overexpressed in aggressive endometrial cancers, has been shown to heterodimerize with HER2 and drive resistance to anti-HER2 therapies in other cancers. We investigated this interaction in high-risk endometrial cancer and evaluated whether the AXL inhibitor batiraxcept could enhance the therapeutic effect of trastuzumab. Methods: We utilized three high-risk primary endometrial cancer cell lines (ARK1 and ARK2, uterine serous carcinoma; PUC198, grade 3 endometrioid adenocarcinoma). Immunofluorescence and proximity ligation assays were performed on an ARK2 tumor, and proximity ligation assay was performed on PUC198 cells to assess the physical interaction of HER2 and AXL. Cells were treated with vehicle, batiraxcept, trastuzumab, or both, and colony formation, cell viability, and Matrigel invasion assays were used to assess cell proliferation and invasion. Expression levels of 214 proteins implicated in carcinogenesis were measured via reverse phase protein array. Treatments were also administered to mice injected with ARK1 and ARK2, and tumor burden evaluated via dissection. Results: Our results demonstrate that AXL and HER2 co-localize and interact in high-risk endometrial cancer cells. We also showed that batiraxcept addition to trastuzumab decreased cell viability and worked synergistically to reduce cell proliferation and invasion in vitro and tumor burden in vivo. Reverse phase protein array analysis revealed that the proteins HER2, phosphorylated HSP-27, Ki-67, LRG1, and LDH-A were downregulated by trastuzumab, and further downregulated by the combination therapy. Conclusions: Our findings support the combination of batiraxcept and trastuzumab as a promising therapeutic strategy for aggressive HER2+ endometrial cancer.