
Am J Cancer Res 2012;2(4):446-458
Review Article
Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38
mitogen activated protein kinase
James W Antoon, Melyssa R Bratton, Lori M Guillot, Scott Wadsworth, Virgilio A Salvo, Steven Elliott, John A McLachlan, Matthew
E Burow
Department Medicine, Section of Hematology & Medical Oncology, Tulane University School of Medicine, New Orleans, LA
70112; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112; Ethicon, Inc., Somerville NJ
08876, USA
Received May 22, 2012; accepted June 17, 2012; Epub June 28, 2012; Published July 15, 2012
Abstract: Endocrine therapy resistance is a primary cause of clinical breast cancer treatment failure. The p38 mitogen activated
protein kinase (MAPK) signaling pathway is known to promote ligand independent tumor growth and resistance to endocrine
therapy. In this study, we investigated the therapeutic potential of the p38 inhibitor RWJ67657 in the treatment of tamoxifen
resistant MDA-MB-361 cells. RWJ67657 dose-dependently decreased both basal and stimulated activation of p38 MAPK
signaling in this drug resistant cell system. Decreased activation of p38 by RWJ67657 resulted in inhibition of the downstream
p38 targets hsp27 and MAPKAPK. Diminished p38 signaling resulted in inhibition of p38-medated gene transcription.
Furthermore, pharmacological inhibition of p38 by RWJ67657 decreased biological effects of p38, including ER-mediated gene
expression and clonogenic survival in a dose-dependent manner. Animal studies revealed significantly decreased p38 signaling
in vivo following exposure to RWJ67657. Treatment with the inhibitor markedly decreased phosphorylation of p38 in MDA-MB-361
tumors, leading to decreased transcription of both Fra-1 and progesterone receptor. Utilizing well-established xenograft tumor
models, we demonstrated that RWJ67657 exhibits potent anti-tumor properties. Treatment with RWJ67657 markedly decreased
tamoxifen resistant tumor growth, both in the presence and absence of estrogen. Taken together, our findings demonstrate the
therapeutic potential of targeting the p38-MAPK signaling cascade in the treatment of endocrine resistant breast cancer.
(AJCR0000124).
Keywords: p38, mitogen-activated protein kinase, endocrine resistance, breast cancer, drug discovery, cancer biology, hormone
independence, kinase inhibitors, estrogen receptor, gene transcription
Address all correspondence to:
Dr. Matthew E Burow
Tulane University School of Medicine
1430 Tulane Ave, SL-78
New Orleans, LA 70112, USA.
Tel: 504-988-6688; Fax: 504-988-5483
E-mail: mburow@tulane.edu
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