The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
An integrin β3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition
Open accessAbstract
Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)β₃ expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.
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“In fact, integrin αvβ3 can induce apoptosis (Stupack et al., 2001), tumor progression (Desgrosellier et al., 2009), and tumor stemness (Seguin et al., 2014) in an anchorage-independent manner.”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Seguin et al., 2014
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“Interestingly, integrins can also mediate signaling cascades independent of ligand binding.”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Seguin et al., 2014
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Cites
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,922
Integrins in cancer: biological implications and therapeutic opportunities
Desgrosellier, J. S., & Cheresh, D. A. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2748 · Cited by 3,815
Self-citationTumour stem cells and drug resistance
Dean, M., Fojo, T., & Bates, S. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1590 · Cited by 3,668
Cancer stem cells in solid tumours: accumulating evidence and unresolved questions
Visvader, J. E., & Lindeman, G. J. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2499 · Cited by 3,501
Requirement of Vascular Integrin α v β 3 for Angiogenesis
Brooks, P. C., Clark, R. A. F., & Cheresh, D. A. (1994) · Science · doi:10.1126/science.7512751 · Cited by 3,020
Self-citationHermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., Guba, M. O., Bruns, C. J., & Heeschen, C. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.06.002 · Cited by 2,946
A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., McDermott, U., Azizian, N., Zou, L., Fischbach, M. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.02.027 · Cited by 2,770
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer
Singh, A., & Settleman, J. (2010) · Oncogene · doi:10.1038/onc.2010.215 · Cited by 2,545
EGFR Antagonists in Cancer Treatment
Ciardiello, F., & Tortora, G. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0707704 · Cited by 2,095
RAS oncogenes: weaving a tumorigenic web
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3106 · Cited by 1,789
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Metadata
- Authors
- Seguin, L., Kato, S., Franovic, A., Camargo, M. F., Lesperance, J., Elliott, K. C., Yebra, M., Mielgo, A., Lowy, A. M., Husain, H., Cascone, T., Diao, L., Wang, J., Wistuba, I. I., Heymach, J. V., Lippman, S. M., Desgrosellier, J. S., Anand, S., Weis, S. M., & Cheresh, D. A.
- Affiliations
- University of California San Diego (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Cheresh, David A.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2014-04-20
- Volume
- 16
- Issue
- 5
- Pages
- 457-468
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4105198
- OpenAlex
- W2029572050
- Cited by
- 374
- References
- 59
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 22 · 2023: 32 · 2022: 27 · 2021: 36 · 2020: 35 · 2019: 41 · 2018: 28 · 2017: 33 · 2016: 40 · 2015: 34 · 2014: 14
- FWCI
- 19.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- National Institutes of Health
- U.S. Public Health Service (R3750286)
- National Heart, Lung, and Blood Institute (HL 57900, R00HL112962, P01HL057900)
- National Cancer Institute (CA-45726, R01CA045726, CA155620, R01CA155620, R37CA050286, R01CA168692, CA168692, P30CA023100, T32CA121938, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- integrin αvβ3, KRAS, RalB, erlotinib resistance, cancer stemness, cancer stem cells, NF-κB activation, TBK1, bortezomib, anchorage-independent growth, self-renewal, tumor initiation, lung cancer, breast cancer, pancreatic cancer
- MeSH terms
- Erlotinib Hydrochloride, Animals, Female, Humans, Lung Neoplasms, Mice, Nude, Phenotype, Proto-Oncogene Proteins, Quinazolines, Time Factors, Transfection, Tumor Cells, Cultured, Neoplastic Stem Cells, Signal Transduction, Randomized Controlled Trials as Topic, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Clinical Trials, Phase II as Topic, Protein Serine-Threonine Kinases, ras Proteins, Spheroids, Cellular, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-rel, ral GTP-Binding Proteins, Xenograft Model Antitumor Assays, RNA Interference, Integrin alphaVbeta3, Integrin beta3, Cell Line, Tumor, Tumor Burden, Protein Kinase Inhibitors, Cell Proliferation, Mice, Molecular Targeted Therapy, ErbB Receptors
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