Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models.
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.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Chaoxin
C
Hu
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Tikva
T
Dadon
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Venugopal
V
Chenna
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Shinichi
S
Yabuuchi
Merck and Co., Boston, Massachusetts.
Rajat
R
Bannerji
Merck and Co., Boston, Massachusetts.
Robert
R
Booher
Merck and Co., Boston, Massachusetts.
Peter
P
Strack
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Nilofer
N
Azad
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. bnelkin@jhmi.edu amaitra@mdanderson.org.
Barry D
BD
Nelkin
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. bnelkin@jhmi.edu amaitra@mdanderson.org.
Anirban
A
Maitra
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D003497:Cyclic N-Oxides; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004334:Drug Administration Schedule; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007212:Indolizines; D007274:Injections, Intraperitoneal; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D006575:Heterocyclic Compounds, 3-Ring; D007212:Indolizines; C548887:MK 2206; D011726:Pyridinium Compounds; D016160:Retinoblastoma Protein; C553669:dinaciclib; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; C495905:CDK5 protein, human