TY - JOUR
T1 - NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma
AU - Yamaguchi, Tomoya
AU - Yanagisawa, Kiyoshi
AU - Sugiyama, Ryoji
AU - Hosono, Yasuyuki
AU - Shimada, Yukako
AU - Arima, Chinatsu
AU - Kato, Seiichi
AU - Tomida, Shuta
AU - Suzuki, Motoshi
AU - Osada, Hirotaka
AU - Takahashi, Takashi
N1 - Funding Information:
We thank T. Hunter and S.J. Shattil for providing the c-Src constructs and N. Taniguchi for the ERBB3 construct. This work was supported in part by grants-in-aid for Scientific Research on Priority Areas and Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, as well as grants-in-aid for Scientific Research (A) and Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS).
PY - 2012/3/20
Y1 - 2012/3/20
N2 - We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an " Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.
AB - We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an " Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.
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U2 - 10.1016/j.ccr.2012.02.008
DO - 10.1016/j.ccr.2012.02.008
M3 - Article
C2 - 22439932
AN - SCOPUS:84863384604
SN - 1535-6108
VL - 21
SP - 348
EP - 361
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
