Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor.
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.
Sakurama
Kazufumi
K
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, and Okayama Citizens' Hospital, 2-5-1 Shikatacho, Okayama 700-9558, Japan.
Noma
Kazuhiro
K
Takaoka
Munenori
M
Tomono
Yasuko
Y
Watanabe
Nobuyuki
N
Hatakeyama
Shinji
S
Ohmori
Osamu
O
Hirota
Seiichi
S
Motoki
Takayuki
T
Shirakawa
Yasuhiro
Y
Yamatsuji
Tomoki
T
Haisa
Minoru
M
Matsuoka
Junji
J
Tanaka
Noriaki
N
Naomoto
Yoshio
Y
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D013379:Substrate Specificity
D001549:Benzamides; D009025:Morpholines; D010879:Piperazines; D011743:Pyrimidines; C524632:TAE226; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt