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.

A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors

“…A number of marine-derived kinase inhibitors have entered clinic trials, and some are already in later pre-approval stages or have been recently approved (Figure 27 and Figure 28 and Table 7). For example, plitidepsin (aplidin) is a marine natural product that was developed by the Spanish company PharmaMar as an inhibitor of EGPR, Src, JNK and p38 MAPK and, although there were dose-limiting toxicities in some cases, it was not fully withdrawn from clinical trials during phase II [124,125,126]. Later, it was approved for clinical use in Australia in 2018 for the treatment of relapsed/refractory multiple myeloma patients.…”

Phase I–II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma

“…Furthermore, the elimination of p27kip1 in these cells (by siRNA) or in mouse embryo fibroblasts (MEFs; p27 kip1 knockout) increases their sensitivity to plitidepsin (Moneo et al , 2007). Phosphorylated JNK has recently been described as a pharmacodynamic biomarker of plitidepsin in xenografted tumours as well as in normal surrogate tissues (Munoz-Alonso et al , 2013). …”

Development of Marine-Derived Compounds for Cancer Therapy

“…It shows pro-oncogenic activities and is usually overexpressed in many tumors, such as multiple myeloma, breast cancer and lung cancer [32]. Moreover, plitidepsin can also inhibit the cell cycle and cause apoptosis via G1 and G2/M arresting and sustained activation of the Rac1/JNK pathway [19][20][21]. Finally, plitidepsin was also found to induce proteotoxic apoptosis by generating endoplasmic reticulum stress and inhibiting autophagy [22].…”