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Sorafenib Inhibits Non–Small Cell Lung Cancer Cell Growth by Targeting B-RAF in KRAS Wild-Type Cells and C-RAF in KRAS Mutant Cells

¹ Department of Medical Oncology, Kinki University School of Medicine; ² Department of Medical Oncology, Kinki University School of Medicine, Sakai Hospital, Osaka, Japan

Requests for reprints: Isamu Okamoto, Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan. Phone: 81-72-366-0221; Fax: 81-72-360-5000; E-mail: chi-okamoto{at}dotd.med.kindai.ac.jp.

Key Words: sorafenib • non–small cell lung cancer • B-RAF • C-RAF • KRAS

Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non–small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G₁ arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G₁ arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G₁ arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G₁ arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G₁ arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [Cancer Res 2009;69(16):6515–21]