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PNAS 110 (11): 4339-4344

Copyright © 2013 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

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

Akio Iwanamia, Beatrice Ginib,c,1, Ciro Zancab,1, Tomoo Matsutanib, Alvaro Assuncaod, Ali Naele, Julie Dangf, Huijun Yangb, Shaojun Zhug, Jun Kohyamag, Issay Kitabayashih, Webster K. Caveneeb,i, Timothy F. Cloughesyj, Frank B. Furnarib,i,k, Masaya Nakamuraa, Yoshiaki Toyamaa, Hideyuki Okanol, and Paul S. Mischelb,i,k,2

Departments of aOrthopaedic Surgery and lPhysiology, Keio University School of Medicine, Tokyo 160-8582, Japan; bLudwig Institute for Cancer Research, iMoores Comprehensive Cancer Center, and kDepartment of Pathology, University of California at San Diego, La Jolla, CA 92093; cDepartment of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, 37134 Verona, Italy; dUndergraduate Minor in Biomedical Research Program, and Departments of gMolecular and Medical Pharmacology and jNeurology, University of California, Los Angeles, CA 90095; eDepartment of Pathology, University of California, Irvine, CA 92697; fSchool of Pharmacy, University of California, San Francisco, CA 94104; and hDivision of Hematological Malignancy, National Cancer Center Research Institute, Tokyo 104-0045, Japan

Edited{dagger} by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved February 1, 2013 (received for review October 12, 2012)

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.

Key Words: mTORC1 • glioma


Freely available online through the PNAS open access option.

Author contributions: A.I., B.G., C.Z., W.K.C., T.F.C., F.B.F., and P.S.M. designed research; A.I., B.G., C.Z., T.M., A.A., A.N., J.D., H.Y., S.Z., and J.K. performed research; C.Z., T.M., I.K., and F.B.F. contributed new reagents/analytic tools; A.I., B.G., C.Z., T.M., W.K.C., T.F.C., F.B.F., M.N., Y.T., H.O., and P.S.M. analyzed data; and A.I., B.G., C.Z., T.M., W.K.C., T.F.C., F.B.F., M.N., Y.T., H.O., and P.S.M. wrote the paper.

1B.G. and C.Z. contributed equally to this work.

The authors declare no conflict of interest.

{dagger}This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1217602110/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: pmischel{at}ucsd.edu.


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