Another MEK inhibitor, selumetinib (AZD6244, AstraZeneca), showed no superior effect in pancreatic cancer patients when compared with conventional cytotoxic chemotherapy.
#Compusyn trial#
CI-1040, developed by Pfizer/Warner-Lambert, was the first MEK inhibitor that progressed to the clinical stage of evaluation but failed in a phase II trial due to its poor exposure ( number, NCT00033384). However, few MEK inhibitors have been developed and applied in clinical trials for pancreatic cancer to date. Thus, targeting the MAPK pathway appears to be a valuable strategy for the treatment of pancreatic cancer. Activation of the Ras-Raf-MEK-ERK pathway promotes cell cycle progression through increasing cyclin D expression and inhibits apoptosis by repressing the pro-apoptotic Bcl-2 family of proteins. Furthermore, cooperation of the Ras-Raf-MEK-ERK pathway with other genetic alterations, including p16 INK4a, p53, or TGFβ/SMAD4, accelerates pancreatic cancer progression. In transgenic mouse models, K-Ras mutation has been shown to play an early oncogenic role in the development and progression of pancreatic cancer. K-Ras mutations are present in approximately 95% of pancreatic cancers, leading to burst activation of the mitogen-activated protein kinase (MAPK) pathway, also known as the Ras-Raf-MEK-ERK pathway. Mutations of oncogenic genes are largely associated with triggering cancer cell proliferation, metastasis, and angiogenesis. Therefore, development of a new therapeutic strategy for pancreatic cancer is an urgent clinical challenge.
Recently, the combination of 5-fluorouracil, irinotecan, and oxaliplatin was shown to provide a significant increase of the overall survival rate (11.1 months) for patients with pancreatic cancer but was also associated with a high toxicity rate. Gemcitabine is used as a standard chemotherapy but only improves overall survival by 5.7 months, while the combination of gemcitabine with the targeted therapy erlotinib only enhances overall survival by 6.24 months. Compounding this poor prognosis is the limited therapeutic options against pancreatic cancer. The overall 5-year survival rate for patients with pancreatic cancer is less than 5%. Pancreatic cancer accounts for 3% of all cancers but remains the fourth leading cause of cancer-related deaths. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. The AsPC-1 xenograft was used to assess antitumor effects in vivo.
The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression.
0 kommentar(er)
