Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Clin Invest. 2012 Jul;122(7):2637-51. doi: 10.1172/JCI62058. Epub 2012 Jun 1.

Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response.

Author information

  • 1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.

Abstract

EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR-based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma.

PMID:
22653055
[PubMed - indexed for MEDLINE]
PMCID:
PMC3386822
Free PMC Article

Publication Types, MeSH Terms, Substances, Supplementary Concepts, Grant Support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Journal of Clinical Investigation Icon for PubMed Central
    Loading ...
    Write to the Help Desk