title: NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma.
abstract: 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.
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Ryoji
authors.initials: R
authors.lastname: Sugiyama
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Hosono
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Arima
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kato
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.forename: Motoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D016392:Proto-Oncogene Proteins pp60(c-src)