التفاصيل البيبلوغرافية
العنوان:
Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models
المؤلفون:
Rajat Bannerji , Venugopal Chenna , Anirban Maitra , Nilofer A Azad , Shinichi Yabuuchi , Peter Strack , Tikva Dadon , Robert Booher , Barry D. Nelkin , Chaoxin Hu
سنة النشر:
2015
مصطلحات موضوعية:
Cancer Research , Administration, Oral , Mice, Nude , Apoptosis , Pyridinium Compounds , medicine.disease_cause , Retinoblastoma Protein , Article , Drug Administration Schedule , Metastasis , Cyclic N-Oxides , chemistry.chemical_compound , Pancreatic tumor , Cyclin-dependent kinase , Pancreatic cancer , Antineoplastic Combined Chemotherapy Protocols , Medicine , Animals , Humans , Dinaciclib , Neoplasm Metastasis , Phosphorylation , Cell Proliferation , biology , business.industry , Indolizines , Cyclin-Dependent Kinase 5 , medicine.disease , Bridged Bicyclo Compounds, Heterocyclic , Immunohistochemistry , Xenograft Model Antitumor Assays , Tumor Burden , Pancreatic Neoplasms , Treatment Outcome , Oncology , chemistry , MK-2206 , Cancer research , biology.protein , KRAS , business , Heterocyclic Compounds, 3-Ring , Proto-Oncogene Proteins c-akt , CDK inhibitor , Injections, Intraperitoneal
الوصف:
KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5) reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., three times a week) and MK-2206 (60 mg/kg, orally, three times a week) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI–CTEP-approved multicenter phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened. Mol Cancer Ther; 14(7); 1532–9. ©2015 AACR.
اللغة:
English
URL الوصول:
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c1a7f8eb1f8692e1ed8b98e78e6be830 https://europepmc.org/articles/PMC4497872 /
Rights:
OPEN
رقم الانضمام:
edsair.doi.dedup.....c1a7f8eb1f8692e1ed8b98e78e6be830
قاعدة البيانات:
OpenAIRE