Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor

Kazufumi Sakurama, Kazuhiro Noma, Munenori Takaoka, Yasuko Tomono, Nobuyuki Watanabe, Shinji Hatakeyama, Osamu Ohmori, Seiichi Hirota, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Minoru Haisa, Junji Matsuoka, Noriaki Tanaka, Yoshio Naomoto

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60 Citations (Scopus)

Abstract

Focal adhesion kinase (FAK) is often up-regulated in a variety of malignancies, including gastrointestinal stromal tumor (GIST), and its overexpression seems to be associated with tumor progressiveness and poor prognosis. GIST is well known to have a mutation to c-KIT; thus, a specific c-KIT inhibitor (imatinib) is recognized as the first-line chemotherapy for GIST, although a certain type of c-KIT mutation reveals a resistance to imatinib due to as yet uncertain molecular mechanisms. To assess the c-KIT mutation-related variation of cellular responses to imatinib, murine lymphocyte-derived Ba/F3 cells, which are stably transduced with different types of c-KIT mutation, were treated with either imatinib or a FAK inhibitor (TAE226), and their antitumor effects were determined in vitro and in vivo. A mutation at exon 11 (KITdel559-560) displayed a high sensitivity to imatinib, whereas that at exon 17 (KIT820Tyr) showed a significant resistance to imatinib in vitro and in vivo. KIT820Tyr cells appeared to maintain the activities of FAK and AKT under the imatinib treatment, suggesting that FAK might play a role in cell survival in imatinib-resistant cells. When FAK activity in those cells was inhibited by TAE226, cell growth was equally suppressed and the cells underwent apoptosis regardless of the c-KIT mutation types. Oral administration of TAE226 significantly diminished tumor growth in nude mice bearing KIT820Tyr xenografts. In summary, c-KIT mutation at exon 17 displayed a resistance to imatinib with maintained activations of FAK and subsequent survival signals. Targeting FAK could be a potential therapeutic strategy for imatinib-resistant GISTs.

Original languageEnglish
Pages (from-to)127-134
Number of pages8
JournalMolecular cancer therapeutics
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sakurama, K., Noma, K., Takaoka, M., Tomono, Y., Watanabe, N., Hatakeyama, S., Ohmori, O., Hirota, S., Motoki, T., Shirakawa, Y., Yamatsuji, T., Haisa, M., Matsuoka, J., Tanaka, N., & Naomoto, Y. (2009). Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor. Molecular cancer therapeutics, 8(1), 127-134. https://doi.org/10.1158/1535-7163.MCT-08-0884