TY - JOUR
T1 - Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer
AU - Kogita, Akihiro
AU - Togashi, Yosuke
AU - Hayashi, Hidetoshi
AU - Banno, Eri
AU - Terashima, Masato
AU - De Velasco, Marco A.
AU - Sakai, Kazuko
AU - Fujita, Yoshihiko
AU - Tomida, Shuta
AU - Takeyama, Yoshifumi
AU - Okuno, Kiyotaka
AU - Nakagawa, Kazuhiko
AU - Nishio, Kazuto
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.
AB - Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.
KW - Alectinib
KW - Crizotinib
KW - EML4-ALK rearrangement
KW - MET
KW - Non-small cell lung cancer
UR - http://www.scopus.com/inward/record.url?scp=84921934141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921934141&partnerID=8YFLogxK
U2 - 10.3892/ijo.2014.2797
DO - 10.3892/ijo.2014.2797
M3 - Article
C2 - 25502629
AN - SCOPUS:84921934141
SN - 1019-6439
VL - 46
SP - 1025
EP - 1030
JO - International Journal of Oncology
JF - International Journal of Oncology
IS - 3
ER -
