Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4339-44. doi: 10.1073/pnas.1217602110. Epub 2013 Feb 25.

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.

Author information

1
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.

Abstract

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.

PMID:
23440206
PMCID:
PMC3600508
DOI:
10.1073/pnas.1217602110
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

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