Preclinical development of CXCR6 antagonists to target sorafenib resistance in Hepatocellular Carcinoma

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PROJECT SUMMARY/ABSTRACT Sorafenib (Nexavar®) is the first FDA approved targeted drug for advanced hepatocellular carcinoma (HCC) patients and a first-line treatment. However, it offers only a moderate life extension in about 40% of advanced unresectable HCC patients due to low response rate, serious adverse events and acquired resistance. Some of the cellular pathways associated with HCC development and poor prognosis also cause resistance to sorafenib. Understanding which pathway will have monumental impact by providing HCC specific clinical biomarkers of response and the development of new therapeutic targets. One such pathway dysregulated in 50% of HCCs is the activation of Wnt/β-catenin, induced by kinase cascades, notably the Ras/Raf/Mek/Erk (targeted by sorafenib), PI3K/AKT/TOR and p38 MAPK leading to inactivation of GSK-3β kinase. Post its escape from phosphorylation by GSK-3β and proteasomal degradation, β-catenin accumulates in the nucleus and activates transcription of several oncogenic proteins rendering sorafenib ineffective and promotes unchecked anti-apoptosis, cell proliferation, angiogenesis, EMT and invasion. A novel strategy proposed by us for combating resistance to sorafenib involves inhibiting hyperactivation of a chemokine receptor CXCR6. Signaling from CXCR6 and its ligand CXCL16 drives resistance to sorafenib through the downstream kinases and culminates at Ser-9 phospho-GSK3β/β-catenin activation. CXCR6-knockdown in SK-Hep-1 and other hepatoma cell lines is correlated with lower p38 activity, increased GSK3β activity, membrane sequestration of β-catenin and downregulation of β-catenin transcriptional activity in the nucleus. We have developed a first-in-class small molecule lead, SBI-457, that antagonizes the CXCR6 receptor, is orally bioavailable in mice and efficacious at attenuating tumor growth in a 30-day mouse xenograft model for advanced HCC with no adverse effects. Since CXCR6/CXCL16 are not highly expressed in non-cancerous hepatocyte and other liver tissue, SBI-457 is expectedly non-toxic in vivo under high dose and chronic exposure. Since there are no known clinical CXCR6 antagonists to date, optimization of lead SBI-457 as a single agent in advanced HCC will be the first innovative aspect of our application. A second major innovation is a combination of optimized CXCR6 antagonists with sorafenib in resistant HCC cells to understand and then overcome the major bottleneck of chemoresistance. Hence small molecule CXCR6 antagonist leads developed in this application have the potentially to expand the clinical use of sorafenib and other targeted agents by re-sensitization, improved response, and lowering of the dose thereby reducing toxicity and risk of adverse events.