Regorafenib Inhibits Sorafenib-Resistant HCC Cell Growth
BOSTON, MA—Regorafenib inhibited the growth of sorafenib-resistant hepatocellular carcinoma cells, potentially through the suppression of the ERK signaling pathway, reported researchers at The Liver Meeting® 2016.
Regorafenib is a multi-kinase inhibitor; it targets VEGFRs, PDGFR, FGFR, RAF, and p38 MAP kinase. One previous Phase 3 trial found that regorafenib in patients with unresectable hepatocellular carcinoma (HCC) improved overall survival. But if the role of regorafenib in inhibiting growth in sorafenib-refractory HCC remains unclear.
Therefore, Tomomi Hashiba, from Kanazawa University Graduate School of Medicine Science, Kanazawa, Japan, and coauthors evaluated the impact of regorafenib on sorafenib-naive and sorafenib-resistant HCC cells.
The team obtains 2 HCC cells lines (Huh1 and Huh7) and 2 primary HCC cells from surgically resected specimens. They also established an HCC cell line (KH) from a STORM trial participant who had received sorafenib and developed HCC.
Mutations were detected through whole exome sequencing and protein expression of phospho-Akt (Ser 4730), -STAT3, and -Erk was evaluated with Western blotting.
The efficacy of sorafenib 30mg/kg/day and regorafenib 20mg/kg/day was assessed via a subcutaneous xenotransplantation model on sorafenib-resistant clones in vivo.
"Regorafenib inhibited the growth of sorafenib-resistant HCC cells," reported Dr. Hashiba. "However, regorafenib and sorafenib showed similar anti-tumor effects in sorafenib-naive HCC cells. The efficacy of regorafenib on the sorafenib-resistant clones suggests its potential utility as a second-line treatment in HCC patients who showed progression after initial sorafenib treatment."
KH cells demonstrated chemosensitivities to regorafenib but not sorafenib in vitro. Analysis of protein expression suggested that sorafenib had no effect on suppression of Akt, Erk, and STAT3 signaling pathways, noted Dr. Hashiba.
Regorafenib suppressed STAT3 and Erk signaling in sorafenib-resistant (but not sorafenib-naive) KM cells.
Common mutations, including sorafenib target genes BRAF, KIT, PDGFR, and STAT3, were not detected in sorafenib-resistant clones. MAPK or PI3K-mTOR pathway gene mutations were found only in KH cells.
"In sorafenib-naive Huh7 cells, the effect of regorafenib is similar to that of sorafenib," reported Dr. Hashiba. "In contrast, regorafenib suppressed the subcutaneous tumor growth of sorafenib-resistant Huh7 xenograft in vivo compared with sorafenib."