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

Ken Takezawa, Isamu Okamoto, Kimio Yonesaka, Erina Hatashita, Yuki Yamada, Masahiro Fukuoka, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

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Abstract

Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK)si gnaling 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.

Original languageEnglish
Pages (from-to)6515-6521
Number of pages7
JournalCancer Research
Volume69
Issue number16
DOIs
Publication statusPublished - Aug 15 2009
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Growth
Extracellular Signal-Regulated MAP Kinases
Phosphorylation
sorafenib
Cyclin E
RNA Interference
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

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. / Takezawa, Ken; Okamoto, Isamu; Yonesaka, Kimio; Hatashita, Erina; Yamada, Yuki; Fukuoka, Masahiro; Nakagawa, Kazuhiko.

In: Cancer Research, Vol. 69, No. 16, 15.08.2009, p. 6515-6521.

Research output: Contribution to journalArticle

Takezawa, Ken ; Okamoto, Isamu ; Yonesaka, Kimio ; Hatashita, Erina ; Yamada, Yuki ; Fukuoka, Masahiro ; Nakagawa, Kazuhiko. / 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. In: Cancer Research. 2009 ; Vol. 69, No. 16. pp. 6515-6521.
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