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Research Articles

Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth

¹ Lineberger Comprehensive Cancer Center, Departments of ² Dermatology and ³ Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and ⁴ NexusPharma, Inc., Langhorne, Pennsylvania

Requests for reprints: Janiel M. Shields, Lineberger Comprehensive Cancer Center, Department of Pharmacology, University of North Carolina at Chapel Hill, CB# 7295, Chapel Hill, NC 27599-7295. Phone: 919-962-1057; Fax: 919-966-0162. E-mail: shieldsj{at}med.unc.edu

Abstract

Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH₂-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas. [Mol Cancer Ther 2007;6(8):2220–9]

Grant support: NIH grants CA42978 and CA69577 (C.J. Der) and CA102096 (N.E. Thomas) and Department of Defense grant DAMD17-00-1-0552 (J.M. Shields).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Unpublished data.

Received 11/27/06; revised 5/ 8/07; accepted 6/13/07.