n-(3-4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2-3-dihydroxypropyl)cyclopropane-1-sulfonamide and Carcinoma--Hepatocellular

Sorafenib is the only approved systemic treatment for advanced hepatocellular carcinoma patients and all the recently published randomized controlled trials on new systemic drugs have been unsuccessful. This is likely due to a lack of understanding of tumor progression, molecular drivers, and liver toxicity, as well as flaws in trial design. An important signaling pathway in hepatocarcinogenesis is the MEK cascade involved in various cellular responses, including adaptation and survival. A key role in this cascade is played by MEK, of which MEK 1/2 represent the prototypes and an interesting target for new oncological drugs. This review analyzes recent developments and future perspectives on the role of MEK inhibitors in hepatocellular carcinoma treatment.

Topics: Antineoplastic Agents; Benzimidazoles; Carcinoma, Hepatocellular; Diphenylamine; Humans; Liver Neoplasms; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Sorafenib; Sulfonamides

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; beta Catenin; Carcinoma, Hepatocellular; Circulating Tumor DNA; Diphenylamine; Disease-Free Survival; Female; Humans; Liver Neoplasms; Male; MAP Kinase Kinase Kinases; Middle Aged; Mutation; Protein Kinase Inhibitors; ras Proteins; Sorafenib; Sulfonamides; Telomerase; Tumor Suppressor Protein p53

There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).. Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥ 2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.. Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.. Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Biomarkers; Carcinoma, Hepatocellular; Diphenylamine; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Sorafenib; Sulfonamides; Treatment Outcome

Mutations affecting the Wnt/β‑catenin pathway have been identified in 26‑40% of hepatocellular carcinoma (HCC) cases. Aberrant activation of this pathway leads to uncontrolled cell proliferation and survival. Thus, identifying Wnt/β‑catenin pathway inhibitors may benefit a subset of patients with HCC. In the present study, the effects of sorafenib and a MEK inhibitor on tumor growth and Wnt/β‑catenin signaling in HCC models were evaluated. A β‑catenin mutant and β‑catenin wild‑type HCC models were treated once daily with i) 10 mg/kg sorafenib, ii) 15 mg/kg refametinib (or 25 mg/kg selumetinib), or iii) sorafenib/refametinib. Western blotting was employed to determine changes in biomarkers relevant to Wnt/β‑catenin signaling. Apoptosis, cell proliferation and β‑catenin localization were analyzed by immunohistochemistry. Sorafenib/refametinib markedly inhibited tumor growth and cell proliferation, and caused cell death in naïve and sorafenib‑resistant HCC models. Despite similar total β‑catenin levels, significant reductions in phosphorylated (p)‑RanBP3 Ser58, p‑β‑catenin Tyr142, active β‑catenin and β‑catenin target genes were observed in sorafenib/refametinib‑treated tumors. Greater levels of β‑catenin in sorafenib/refametinib‑treated tumors were accumulated at the membrane, as compared with in the control. In vitro, sorafenib/refametinib inhibited the Wnt/β‑catenin pathway and suppressed Wnt‑3A‑induced p‑low‑density lipoprotein receptor‑related protein 6 Ser1490, p‑RanBP3 Ser58 and p‑β‑catenin Tyr142 in HCC cells. Combination of sorafenib and refametinib inhibits the growth of naïve and sorafenib resistant HCC tumors in association with active suppression of β‑catenin signaling regardless of β‑catenin mutational status. Thus, the sorafenib/MEK inhibitor combination may represent an alternative treatment for patients with HCC whose tumors develop resistance to sorafenib therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Hepatocellular; Diphenylamine; Humans; Liver Neoplasms; Male; Mice; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Sorafenib; Sulfonamides; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials, Phase II as Topic; Diphenylamine; Humans; Liver Neoplasms; Mutation; ras Proteins; Sorafenib; Sulfonamides

The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species.. Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed.. BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo.. BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

Topics: Allografts; Allosteric Regulation; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Diphenylamine; Drug Synergism; Female; Heterografts; Humans; Liver Neoplasms; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Niacinamide; Phenylurea Compounds; Rats; Sorafenib; Sulfonamides