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 journalArticlepeer-review

64 Citations (Scopus)

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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this