Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations

Abstract

The Raf/MEK/ERK pathway is an important mediator of tumor cell proliferation and angiogenesis. Here, we investigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC(50) in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G(1)-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27(KIP1)) and apoptosis (Bcl-2 and survivin) regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma.

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

“…The MAPK pathway regulates ERCC1 protein levels following cisplatin treatment in human melanoma cells A specific inhibitor of MEK1/2 (PD0325901; Ciuffreda et al, 2009) was used to determine the requirement for ERK activation in the cisplatin induction of ERCC1. Human melanoma A375 cells were treated with cisplatin (6 mM), PD0325901 (1 mM), or both cisplatin and PD0325901 for 24, 48 and 72 h and the protein lysates obtained were western blotted to determine the levels of p-ERK and ERCC1 ( Figure 2a).…”

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

“…PD0325901 is the congener of CI-1040, which was found through replacing the hydroxyl and fluorine of CI-1040. It was also to optimize diphenylamine of CI-1040 through pharmacological probe in the study of the Ras/Raf/MEK/ERK signaling pathway (66). To improve the poor solubility and rapid clearance of CI-1040, the diphenylamine core and the hydroxamate side chain were optimized with resulting improvements in solubility, potency in cell-based assays and oral bioavailability.…”

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

“…PMEL17 and EDNRB, are suppressed by MAPK signaling (24)(25)(26)(27). As the expression level of a cell surface target can affect the efficacy of an ADC, we evaluated the suitability of combining the anti-EDNRB ADC with the BRAF inhibitors PLX4032 (28) and G590945 and 2 chemically distinct MEK inhibitors GDC-0973 and GDC-0623.…”