Novel Small-molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of Breast Cancer Cells
2016
Recent evidence indicates that cancer cells, even in the absence of a primary tumor, recirculate from established secondary lesions to further seed and colonize skeleton and soft-tissues, thus expanding metastatic dissemination and precipitating the clinical progression to terminal disease. Recently, we reported that breast cancer cells utilize the chemokine receptor CX3CR1 to exit the blood circulation and lodge to the skeleton of experimental animals. Now we show that CX3CR1 is overexpressed in human breast tumors and skeletal metastases. To assess the clinical potential of targeting CX3CR1 in breast cancer, a functional role of CX3CR1 in metastatic seeding and progression was first validated using a neutralizing antibody for this receptor and transcriptional suppression by CRISPR-interference (CRISPRi). Successively, we synthesized and characterized JMS-17-2, a potent and selective small-molecule antagonist of CX3CR1, which was used in pre- clinical animal models of seeding and established metastasis. Finally, transcriptome analyses of metastatic tissues by Nanostring technology were used to identify cancer-related genes that could mechanistically sustain CX3CR1 pro-metastatic activity. Importantly, counteracting CX3CR1 activation impairs the lodging of Circulating Tumor Cells (CTCs) to the skeleton and soft-tissue organs and also negatively affects further growth of established metastases. Furthermore, nine genes were identified that were similarly altered by JMS-17-2 and CRISPRi and could sustain CX3CR1 pro-metastatic activity. In conclusion, these data support the drug development of CX3CR1 antagonists and promoting their clinical use will provide novel and effective tools to prevent or contain the progression of metastatic disease in breast cancer patients. Implications: This works conclusively validates the instrumental role of CX3CR1 in the seeding of circulating cancer cells and is expected to pave the way for pairing novel inhibitors of this receptor with current standards of care for the treatment of breast cancer patients.
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