Targeting AXL Inhibits the Growth and Metastasis of Prostate Cancer in Bone.

PURPOSE: After failing primary and secondary hormonal therapy, castration-resistant and neuroendocrine prostate cancer metastatic to the bone is invariably lethal, although treatment with docetaxel and carboplatin can modestly improve survival. Therefore, agents targeting biologically relevant pathways in prostate cancer and potentially synergizing with docetaxel and carboplatin in inhibiting bone metastasis growth are urgently needed. EXPERIMENTAL DESIGN: Phosphorylated (activated) AXL expression in human prostate cancer bone metastases was assessed by IHC staining. We evaluated the effects of a novel soluble AXL signaling inhibitor, sAXL (batiraxcept or AVB-S6-500), on tumor growth and lung metastases in prostate cancer patient-derived xenograft models that were implanted intratibially. After injection of LuCaP cells into the tibiae, tumors were treated with batiraxcept and docetaxel or carboplatin alone or in combination, and tumor growth was monitored by serum prostate-specific antigen or bioluminescence. Tumor burden was quantified by human-specific Ku70 staining, and metastasis to the lungs was determined using qPCR. Transcriptomic profiling, Western blotting, and immunohistochemistry were performed to identify treatment-regulated gene and protein profile changes. RESULTS: High AXL phosphorylation in human prostate cancer bone metastases correlated with shortened survival. Batiraxcept alone or in combination with docetaxel or carboplatin significantly suppressed intratibial tumor growth and suppressed metastasis to the lungs through multiple mechanisms, including repression of cancer stemness genes (CD44, ALDH1A1, TACSTD2, and ATXN1) and the PI3K, JAK, MAPK, and E2F1/NUSAP1 signaling pathways. CONCLUSIONS: Our study provides a robust preclinical rationale and mechanisms of action for using batiraxcept as a single agent or in combination with docetaxel or carboplatin to treat lethal metastatic prostate cancer.