Potent Antimyeloma Activity of a Novel ERK5/CDK Inhibitor

Abstract

Purpose: To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug. Experimental Design: Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02.Results: TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1.Conclusions: TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients.

MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

“…To date, several small-molecule inhibitors have been designed to specifically target the MEK5/ERK5 pathway [26, 27, 48]. Equally important, TG02, a new oral pyrimidine-based multikinase inhibitor [49, 50], is also known to directly block ERK5 activity [51]. In fact, this promising antitumor agent is currently undergoing phase I trials in leukemia and multiple myeloma patients, providing the first clues to the benefits of targeting the MEK5/ERK5 cascade in clinical practice, and encouraging other ERK5-specific inhibitors such as XMD8-92 to progress into clinical evaluation.…”

TG02 inhibits proteasome inhibitor–induced HSF1 serine 326 phosphorylation and heat shock response in multiple myeloma

“…Consistent with previous findings, the combination of TG02 and bortezomib results in a strong additive effect on apoptosis, and we confirm our previous findings that the combination of TG02 and carfilzomib results in an additive effect in MM.1s cells ( Figure 2B). 10,13 We observe that TG02 strongly inhibits PI-pS326, PI-induced HSP27 upregulation, and PI-induced HSP40 upregulation in H929 cells ( Figure 2C, left). TG02 also inhibits PI-pS326 in U266 cells but does not lead to HSP inhibition ( Figure 2C, right).…”

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

“…Curiously, two studies unveiled a potential novel MEK5-independent ERK5 activation pathway that occurs during mitosis and relies on cyclin-dependent kinases (CDKs), being particularly relevant during the G2-M phase transition [9,10]. Beyond this discovery, a new cross-talk mechanism within MAPK family members has been proposed, in which active ERK1/2 phosphorylates ERK5 at the Thr732 residue in the C-terminal domain, without the typical activation of the N-terminal kinase domain, and is able to direct ERK5 to the nucleus [11] (Fig.…”

“…This is highlighted by the fact that ERK5 is essential for the protection of reactive oxygen species (ROS)-induced apoptosis in ALL leukaemic cells [69], proliferation of AML cells [69,70], and resistance to therapeutics [71]. Furthermore, ERK5 inhibition blocked proliferation and induced apoptosis [10,[69][70][71], increased cell death by NK cells as a consequence of decreased MHC-I expression [72], and sensitised leukaemic cells to cytarabine-induced apoptosis [73]. However, all these studies focused on the survival and apoptosis of cancer cells after ERK5 inhibition, rather than on its role in cell differentiation.…”