An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition

Nat Cell Biol. 2014 May;16(5):457-68. doi: 10.1038/ncb2953. Epub 2014 Apr 20.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clinical Trials, Phase II as Topic
  • Drug Resistance, Neoplasm* / genetics
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Female
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Molecular Targeted Therapy
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-rel / antagonists & inhibitors
  • Proto-Oncogene Proteins c-rel / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Quinazolines / therapeutic use
  • RNA Interference
  • Randomized Controlled Trials as Topic
  • Signal Transduction / drug effects
  • Spheroids, Cellular
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • ITGB3 protein, human
  • Integrin alphaVbeta3
  • Integrin beta3
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-rel
  • Quinazolines
  • Ralb protein, human
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ral GTP-Binding Proteins
  • ras Proteins

Associated data

  • ClinicalTrials.gov/NCT00409968