title: c-Jun N-terminal kinase phosphorylation is a biomarker of plitidepsin activity.
abstract: Plitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or an acute apoptotic process in which sustained activation of c-Jun N-terminal kinase (JNK) plays a crucial role. With a view to optimizing clinical use of plitidepsin, we have therefore evaluated the possibility of using JNK activation as an in vivo biomarker of response. In this study, we show that administration of a single plitidepsin dose to mice xenografted with human cancer cells does indeed lead to increased phosphorylation of JNK in tumors at 4 to 12 h. By contrast, no changes were found in other in vitro plitidepsin targets such as the levels of phosphorylated-ERK, -p38MAPK or the protein p27KIP1. Interestingly, plitidepsin also increased JNK phosphorylation in spleens from xenografted mice showing similar kinetics to those seen in tumors, thereby suggesting that normal tissues might be useful for predicting drug activity. Furthermore, plitidepsin administration to rats at plasma concentrations comparable to those achievable in patients also increased JNK phosphorylation in peripheral mononuclear blood cells. These findings suggest that changes in JNK activity provide a reliable biomarker for plitidepsin activity and this could be useful for designing clinical trials and maximizing the efficacy of plitidepsin.
authors.affiliation: PharmaMar, Avda. De los Reyes, 1, Pol. Ind. La Mina-Norte, Colmenar Viejo E-28770, Madrid, Spain. mjmunoz@pharmamar.com
authors.forename: María J
authors.initials: MJ
authors.lastname: Muñoz-Alonso
authors.forename: Enrique
authors.initials: E
authors.lastname: Álvarez
authors.forename: María José
authors.initials: MJ
authors.lastname: Guillén-Navarro
authors.forename: Marina
authors.initials: M
authors.lastname: Pollán
authors.forename: Pablo
authors.initials: P
authors.lastname: Avilés
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010456:Peptides, Cyclic; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047630:Depsipeptides; D010456:Peptides, Cyclic; D048031:JNK Mitogen-Activated Protein Kinases; C098980:plitidepsin