title: An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.
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.
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Seguin
authors.affiliation: School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Shumei
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Franovic
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: M Fernanda
authors.initials: MF
authors.lastname: Camargo
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lesperance
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Elliott
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Mayra
authors.initials: M
authors.lastname: Yebra
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
authors.affiliation: Division of Surgical Oncology, Departments of Surgery, San Diego, La Jolla, California 92093, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Hatim
authors.initials: H
authors.lastname: Husain
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Cascone
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Desgrosellier
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Anand
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.affiliation: Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use; D034622:RNA Interference; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C061248:ITGB3 protein, human; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D011799:Quinazolines; C483163:Ralb protein, human; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins; D018631:ras Proteins
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