Targeting AXL inhibits the growth and metastasis of prostate cancer in bone

Abstract

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 PCa 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 immunohistochemical staining. We evaluated the effects of a novel soluble AXL signaling inhibitor, sAXL (batiraxcept or AVB-S6-500), on the tumor growth and lung metastases in PCa patient-derived xenograft models (PDX) that implanted intratibally. 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 PSA or bioluminescence. Tumor burden was quantified by human-specific Ku70 staining, and metastasis to the lung 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 PCa 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 lung through multiple mechanisms, including repression of cancer stemness genes (CD44, ALDH1A1, TACSTD2, 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 mPCa.