Format

Send to

Choose Destination
See comment in PubMed Commons below
Clin Cancer Res. 2013 Jan 15;19(2):380-92. doi: 10.1158/1078-0432.CCR-12-1555. Epub 2012 Dec 4.

c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met.

Author information

1
Departments of Pharmacology & Chemical Biology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Erratum in

  • Clin Cancer Res. 2013 Jul 1;19(13):3715. Thomas, Sufi [added].

Abstract

PURPOSE:

Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance.

EXPERIMENTAL DESIGN:

We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response.

RESULTS:

Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vector-transfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src in HNSCC cell lines was also significantly correlated with erlotinib resistance.

CONCLUSIONS:

Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src.

PMID:
23213056
PMCID:
PMC3549019
DOI:
10.1158/1078-0432.CCR-12-1555
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center