Modeling Targeted Inhibition of MEK and PI3 Kinase in Human Pancreatic Cancer
| Autor: | Jason H. Cheng, Douglas Den Otter, Hani Bou-Reslan, Vidusha Devasthali, Richard A.D. Carano, Emily Chan, Klaus P. Hoeflich, Anne C Clermont, Michelle Nannini, Mallika Singh, Ciara Metcalfe, Mark Merchant, Dorothy French, Joseph Castillo, Melissa R. Junttila, Tim C. Cao, William F. Forrest |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Indazoles medicine.medical_treatment MAP Kinase Kinase 1 medicine.disease_cause Deoxycytidine Models Biological Proto-Oncogene Proteins p21(ras) Mice Piperidines Cell Line Tumor Pancreatic cancer Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Protein Kinase Inhibitors Phosphoinositide-3 Kinase Inhibitors Sulfonamides Chemotherapy Dose-Response Relationship Drug Oncogene business.industry Standard of Care medicine.disease Xenograft Model Antitumor Assays Gemcitabine Pancreatic Neoplasms Regimen Oncology Mutation Cancer research Azetidines KRAS Erlotinib business Carcinoma Pancreatic Ductal medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 14:40-47 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Activating mutations in the KRAS oncogene occur in approximately 90% of pancreatic cancers, resulting in aberrant activation of the MAPK and the PI3K pathways, driving malignant progression. Significant efforts to develop targeted inhibitors of nodes within these pathways are underway and several are currently in clinical trials for patients with KRAS-mutant tumors, including patients with pancreatic cancer. To model MEK and PI3K inhibition in late-stage pancreatic cancer, we conducted preclinical trials with a mutant Kras-driven genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma development. Treatment of advanced disease with either a MEK (GDC-0973) or PI3K inhibitor (GDC-0941) alone showed modest tumor growth inhibition and did not significantly enhance overall survival. However, combination of the two agents resulted in a significant survival advantage as compared with control tumor-bearing mice. To model the clinical scenario, we also evaluated the combination of these targeted agents with gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer. The addition of MEK or PI3K inhibition to gemcitabine, or the triple combination regimen, incrementally enhanced overall survival as compared with gemcitabine alone. These results are reminiscent of the survival advantage conferred in this model and in patients by the combination of gemcitabine and erlotinib, an approved therapeutic regimen for advanced nonresectable pancreatic cancer. Taken together, these data indicate that inhibition of MEK and PI3K alone or in combination with chemotherapy do not confer a dramatic improvement as compared with currently available therapies for patients with pancreatic cancer. Mol Cancer Ther; 14(1); 40–47. ©2014 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|