Abstract
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.
Trial registration:
ClinicalTrials.gov NCT00409968.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Clinical Trials, Phase II as Topic
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Drug Resistance, Neoplasm* / genetics
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Erlotinib Hydrochloride
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Female
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Humans
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Integrin alphaVbeta3 / metabolism
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Integrin beta3 / genetics
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Integrin beta3 / metabolism*
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Molecular Targeted Therapy
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Phenotype
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Protein Kinase Inhibitors / therapeutic use*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-rel / antagonists & inhibitors
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Proto-Oncogene Proteins c-rel / metabolism
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Proto-Oncogene Proteins p21(ras)
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Quinazolines / therapeutic use
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RNA Interference
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Randomized Controlled Trials as Topic
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Signal Transduction / drug effects
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Spheroids, Cellular
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Time Factors
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Transfection
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Tumor Burden / drug effects
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
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ral GTP-Binding Proteins / genetics
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ral GTP-Binding Proteins / metabolism*
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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ITGB3 protein, human
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Integrin alphaVbeta3
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Integrin beta3
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KRAS protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-rel
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Quinazolines
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Ralb protein, human
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Erlotinib Hydrochloride
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EGFR protein, human
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ErbB Receptors
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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Proto-Oncogene Proteins p21(ras)
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ral GTP-Binding Proteins
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ras Proteins
Associated data
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ClinicalTrials.gov/NCT00409968