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

Akio Iwanami, Beatrice Gini, Ciro Zanca, Tomoo Matsutani, Alvaro Assuncao, Ali Nael, Julie Dang, Huijun Yang, Shaojun Zhu, Jun Kohyama, Issay Kitabayashi, Webster K. Cavenee, Timothy F. Cloughesy, Frank B. Furnari, Masaya Nakamura, Yoshiaki Toyam, Hideyuki Okano, Paul S. Mischel

Research output: Contribution to journalArticle

34 Citations (Scopus)

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 downstreammTOR 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.

Original languageEnglish
Pages (from-to)4339-4344
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number11
DOIs
Publication statusPublished - 2013 Mar 12

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Sirolimus
Glioblastoma
Leukemia
Epidermal Growth Factor Receptor
Therapeutics
Cell Death
Neoplasms
Clinical Trials, Phase I
Phosphotransferases
Cell Culture Techniques
Cell Line
Growth
Genes

Keywords

  • Glioma
  • MTORC1

ASJC Scopus subject areas

  • General

Cite this

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. / Iwanami, Akio; Gini, Beatrice; Zanca, Ciro; Matsutani, Tomoo; Assuncao, Alvaro; Nael, Ali; Dang, Julie; Yang, Huijun; Zhu, Shaojun; Kohyama, Jun; Kitabayashi, Issay; Cavenee, Webster K.; Cloughesy, Timothy F.; Furnari, Frank B.; Nakamura, Masaya; Toyam, Yoshiaki; Okano, Hideyuki; Mischel, Paul S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 11, 12.03.2013, p. 4339-4344.

Research output: Contribution to journalArticle

Iwanami, A, Gini, B, Zanca, C, Matsutani, T, Assuncao, A, Nael, A, Dang, J, Yang, H, Zhu, S, Kohyama, J, Kitabayashi, I, Cavenee, WK, Cloughesy, TF, Furnari, FB, Nakamura, M, Toyam, Y, Okano, H & Mischel, PS 2013, 'PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 11, pp. 4339-4344. https://doi.org/10.1073/pnas.1217602110
Iwanami, Akio ; Gini, Beatrice ; Zanca, Ciro ; Matsutani, Tomoo ; Assuncao, Alvaro ; Nael, Ali ; Dang, Julie ; Yang, Huijun ; Zhu, Shaojun ; Kohyama, Jun ; Kitabayashi, Issay ; Cavenee, Webster K. ; Cloughesy, Timothy F. ; Furnari, Frank B. ; Nakamura, Masaya ; Toyam, Yoshiaki ; Okano, Hideyuki ; Mischel, Paul S. / PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 11. pp. 4339-4344.
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