Sakurama, Kazufumi, Noma, Kazuhiro, Takaoka, Munenori, Tomono, Yasuko, Watanabe, Nobuyuki, Hatakeyama, Shinji, Ohmori, Osamu, Hirota, Seiichi, Motoki, Takayuki, Shirakawa, Yasuhiro, Yamatsuji, Tomoki, Haisa, Minoru, Matsuoka, Junji, Tanaka, Noriaki and Naomoto, Yoshio (2009) Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor. Molecular Cancer Therapeutics, 8 (1). pp. 127-134. ISSN 1535-7163

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 KIT(820Tyr) 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.

Item Type:	Article
Additional Information:	author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
Keywords:	FAK; GIST; TAE226; c-KIT mutation; Imatinib
Date Deposited:	14 Dec 2009 13:48
Last Modified:	31 Jan 2013 00:54
URI:	https://oak.novartis.com/id/eprint/1424