Abstract

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin αvβ3 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, αvβ3, 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, αvβ3 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 αvβ3 as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.

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Acknowledgements

We thank D. Shields, E. Murphy, L. Acevedo, S. Advani, M. Huang, I. Tancioni, B. Walsh and A. Larange for helpful discussions. We thank D. Young for his advice and the technical support with the FACS sorter. We thank the Moores Cancer Center Biorepository and H. Howard for their help with the PDXs. We thank J. Camonis for providing RalB constructs. We also thank C. Mirsaidi from Molecular Response LLC for providing the PDXact human lung cancer patient-derived xenograft models used here. D.A.C. was supported by US National Institutes of Health grants CA45726, CA168692, HL57900 and R3750286. A.M.L. was supported by NIH CA155620. S.K. was supported by the National Cancer Institute of the National Institutes of Health under award number T32CA121938. L.S. was supported by the Association pour la Recherche sur le Cancer (ARC) and La Fondation Philippe.

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Affiliations

  1. Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA

    • Laetitia Seguin
    • , Aleksandra Franovic
    • , M. Fernanda Camargo
    • , Jacqueline Lesperance
    • , Kathryn C. Elliott
    • , Mayra Yebra
    • , Ainhoa Mielgo
    • , Jay S. Desgrosellier
    • , Sudarshan Anand
    • , Sara M. Weis
    •  & David A. Cheresh
  2. School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California 92093, USA

    • Shumei Kato
    •  & Hatim Husain
  3. Division of Surgical Oncology, Departments of Surgery, San Diego, La Jolla, California 92093, USA

    • Andrew M. Lowy
  4. Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Tina Cascone
    • , Lixia Diao
    • , Jing Wang
    • , Ignacio I. Wistuba
    •  & John V. Heymach
  5. Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA

    • Scott M. Lippman

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Contributions

L.S. designed and carried out experiments, interpreted data, and wrote the paper; S.K., A.F., J.L., M.Y., M.F.C. and K.C.E. carried out experiments; S.K. provided the lung biopsies. A.M.L. provided the pancreatic PDXs. T.C. and J.V.H provided the H441 model. T.C., J.V.H., L.D., J.W., I.I.W. and J.V.H. provided the BATTLE study. S.M.W., J.S.D., A.M., H.H. and S.A. gave conceptual advice, and S.M.W. and D.A.C. designed experiments, interpreted data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David A. Cheresh.

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https://doi.org/10.1038/ncb2953

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