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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.”
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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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