NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma
Open accessAbstract
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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Frequent bi-allelic SETD2 deletions were identified in fusion-driven LUAD.
“further identified frequent bi-allelic SETD2 deletions in this group127.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [127]
A later study confirmed that somatic TP53 mutations occur less often in LUAD with various oncogenic fusions.
“The key finding that TP53 somatic mutations are underrepresented across LUAD driven by different oncogenic fusions was validated in a subsequent study”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [127]
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- Authors
- Yamaguchi, T., Yanagisawa, K., Sugiyama, R., Hosono, Y., Shimada, Y., Arima, C., Kato, S., Tomida, S., Suzuki, M., Osada, H., & Takahashi, T.
- Affiliations
- Nagoya University (JP)
- Nagoya University Institute for Advanced Research (JP)
- Nagoya University Hospital (JP)
- Aichi Cancer Center Research Institute (JP)
- Corresponding author
- Takahashi, Takashi
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 21
- Issue
- 3
- Pages
- 348-361
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2166836693
- Cited by
- 249
- References
- 47
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 16 · 2023: 16 · 2022: 13 · 2021: 21 · 2020: 15 · 2019: 23 · 2018: 17 · 2017: 21 · 2016: 19 · 2015: 19 · 2014: 18 · 2013: 20 · 2012: 9
- FWCI
- 17.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 994 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- TTF-1, ROR1, lung adenocarcinoma, EGFR, HER3, PI3K/Akt signaling, p38 MAPK, Src kinase, gefitinib resistance, EGFR tyrosine kinase inhibitor resistance
- MeSH terms
- Thyroid Nuclear Factor 1, Adenocarcinoma of Lung, Adenocarcinoma, Humans, Lung Neoplasms, Molecular Sequence Data, Nuclear Proteins, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins pp60(c-src), Receptor Tyrosine Kinase-like Orphan Receptors, ErbB Receptors
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