Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro, in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion: Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC. (Hepatology Communications 2018;2:732‐746)

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

“…One of the main causes of sorafenib resistance in HCC is increased growth factor signaling, including IGF/IGF-1R signaling. Although sorafenib inhibits several tyrosine kinases, it does not suppress IGF-1R phosphorylation in HCC cells [ 232 , 233 ]. Sorafenib treatment of Hep3B, HepG2, or Huh7 cells showed no change in levels of IGF-1R phosphorylation.…”

“…Sorafenib treatment of Hep3B, HepG2, or Huh7 cells showed no change in levels of IGF-1R phosphorylation. Meanwhile, knocking down IGF-1R by shRNA or preventing IGF-1R phosphorylation by ceritinib enhanced the efficacy of sorafenib, reducing cell proliferation rate and tumor development [ 232 ]. Suppression of IGF/IGF-1R signaling induced sorafenib sensitivity in HCC cells.…”

Impact of Integrating Insulin-Like Growth Factor 1 Levels into Model for End-Stage Liver Disease Score for Survival Prediction in Hepatocellular Carcinoma Patients

“…Since blood insulin-like growth factor 1 (IGF-1) is mainly produced by the liver, our previous studies [27][28][29], in line with reports from other groups [30][31][32][33][34], have demonstrated that IGF-1 is a surrogate biomarker for the synthetic function of the liver, the status of underlying chronic liver diseases, and a significant predictor of OS in patients with chronic liver disease and HCC. Moreover, the expression of IGF-1R is upregulated in HCC, and in vitro studies have demonstrated reduction in tumor growth by inhibition of IGF-1 [35][36][37][38]. In accordance with these findings, lower baseline IGF-1 correlates with worse OS in HCC patients, irrespective of liver dysfunction, and data suggest that IGF-1 levels are useful in identifying HCC patients at greater risk of relapse following TACE or liver resection [39,40].…”

ABL1, Overexpressed in Hepatocellular Carcinomas, Regulates Expression of NOTCH1 and Promotes Development of Liver Tumors in Mice

“…All cells were cultured as described previously. 6 For knockdown experiments, Huh7 and Hep3B cells were infected with lentiviral pLKO.1 particles, which contain ABL1, NOTCH1, c-MYC, or scrambled short hairpin RNA (shRNA) and selected with 2 mg/mL puromycin for 5 days. Lentiviral pLKO.1 plasmids for shABL1 (Supplementary Table 1), shNOTCH1 (Supplementary Table 1), shc-MYC, 7 or scrambled shRNA (SHC002; Sigma-Aldrich, St Louis, MO) were packaged with pCMV-dr8.2 (Addgene, Watertown, MA) and pCMV-VSVG (Addgene) in 293T cells to produce lentiviral particles, as described previously.…”

“…The proliferation of these cells was then analyzed using ala-marBlue assay, as described previously. 6 For experiments involving the overexpression of c-MYC, the pBpuro c-MycER retroviral plasmid (gifted from Dr Gerard Evan) 8 and control pBpuro retroviral plasmids (Addgene, #1764) were packaged with pMD.MLV and pMD.G/pVSV.G in 293T cells to produce retroviral particles. Six days after infection with the retroviral particles, scrambled and ABL1-KD Huh7 cells were treated with 100 nM 4-hydroxytamoxifen.…”