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

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

Author information

1
Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
2
School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California 92093, USA.
3
Division of Surgical Oncology, Departments of Surgery, San Diego, La Jolla, California 92093, USA.
4
Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.

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.

PMID:
24747441
PMCID:
PMC4105198
DOI:
10.1038/ncb2953
[Indexed for MEDLINE]
Free PMC Article

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