| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Departments of 1 Dermatology, 2 Pharmacology, 3 Internal Medicine and Medicinal Chemistry, 4 Otolaryngology, and 5 Radiation Oncology, University of Michigan Comprehensive Cancer Center; 6 Ann Arbor V.A. Hospital, Ann Arbor, Michigan; and 7 Van Andel Research Institute, Grand Rapids, Michigan
Requests for reprints: María S. Soengas, University of Michigan Comprehensive Cancer Center (4217 CCGC), 1500 East Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-936-5643, Fax: 734-647-9654; E-mail: soengas{at}umich.edu.
The RAS/BRAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is emerging as a key modulator of melanoma initiation and progression. However, a variety of clinical studies indicate that inhibiting the MAPK pathway is insufficient per se to effectively kill melanoma cells. Here, we report on a genetic and pharmacologic approach to identify survival factors responsible for the resistance of melanoma cells to MEK/ERK antagonists. In addition, we describe a new tumor cell–selective means to bypass this resistance in vitro and in vivo. By generating a panel of isogenic cell lines with specific defects in the apoptotic machinery, we found that the ability of melanoma cells to survive in the absence of functional MEK relies on an ERK-independent expression of the antiapoptotic factor Mcl-1 (and to a lesser extent, Bcl-xL and Bcl-2). Using computer-based modeling, we developed a novel Bcl-2 homology domain 3 (BH3) mimetic. This compound, named TW-37, is the first rationally designed small molecule with high affinity for Mcl-1, Bcl-xL, and Bcl-2. Mechanistic analyses of the mode of action of TW-37 showed a synergistic tumor cell killing in the presence of MEK inhibitors. Importantly, TW-37 unveiled an unexpected role of the MAPK pathway in the control of reactive oxygen species (ROS). This function was critical to prevent the activation of proapoptotic functions of p53 in melanoma cells, but surprisingly, it was dispensable for normal melanocytes. Our results suggest that this MAPK-dependent ROS/p53 feedback loop is a point of vulnerability of melanoma cells that can be exploited for rational drug design. (Cancer Res 2006; 66(23): 11348-59)
This article has been cited by other articles:
|
|
 |
|
  B. D. Zeitlin, I. J. Zeitlin, and J. E. Nor Expanding Circle of Inhibition: Small-Molecule Inhibitors of Bcl-2 as Anticancer Cell and Antiangiogenic Agents J. Clin. Oncol., September 1, 2008; 26(25): 4180 - 4188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Azmi, Z. Wang, R. Burikhanov, V. M. Rangnekar, G. Wang, J. Chen, S. Wang, F. H. Sarkar, and R. M. Mohammad Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis Mol. Cancer Ther., September 1, 2008; 7(9): 2884 - 2893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S.M. Smalley, R. Contractor, T. K. Nguyen, M. Xiao, R. Edwards, V. Muthusamy, A. J. King, K. T. Flaherty, M. Bosenberg, M. Herlyn, et al. Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression Cancer Res., July 15, 2008; 68(14): 5743 - 5752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kumar, K. G. Cordell, J. S. Lee, F. P. Worden, M. E. Prince, H. H. Tran, G. T. Wolf, S. G. Urba, D. B. Chepeha, T. N. Teknos, et al. EGFR, p16, HPV Titer, Bcl-xL and p53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer J. Clin. Oncol., July 1, 2008; 26(19): 3128 - 3137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shangary, K. Ding, S. Qiu, Z. Nikolovska-Coleska, J. A. Bauer, M. Liu, G. Wang, Y. Lu, D. McEachern, D. Bernard, et al. Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer Mol. Cancer Ther., June 1, 2008; 7(6): 1533 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kumar, K. G. Cordell, N. D'Silva, M. E. Prince, M. E. Adams, S. G. Fisher, G. T. Wolf, T. E. Carey, and C. R. Bradford Expression of p53 and Bcl-xL as Predictive Markers for Larynx Preservation in Advanced Laryngeal Cancer Arch Otolaryngol Head Neck Surg, April 1, 2008; 134(4): 363 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Z. Carter, D. H. Mak, W. D. Schober, M. F. Dietrich, C. Pinilla, L. T. Vassilev, J. C. Reed, and M. Andreeff Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5 Blood, April 1, 2008; 111(7): 3742 - 3750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Haass, K. Sproesser, T. K. Nguyen, R. Contractor, C. A. Medina, K. L. Nathanson, M. Herlyn, and K. S.M. Smalley The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel Clin. Cancer Res., January 1, 2008; 14(1): 230 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Danial BCL-2 Family Proteins: Critical Checkpoints of Apoptotic Cell Death Clin. Cancer Res., December 15, 2007; 13(24): 7254 - 7263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kaneko, Z. Zhang, M. G. Mantellini, E. Karl, B. Zeitlin, M. Verhaegen, M. S. Soengas, M. Lingen, R. M. Strieter, G. Nunez, et al. Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth Cancer Res., October 15, 2007; 67(20): 9685 - 9693. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
