title: PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.
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.
authors: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Akio
authors: A
authors: Iwanami
authors: Beatrice
authors: B
authors: Gini
authors: Ciro
authors: C
authors: Zanca
authors: Tomoo
authors: T
authors: Matsutani
authors: Alvaro
authors: A
authors: Assuncao
authors: Ali
authors: A
authors: Nael
authors: Julie
authors: J
authors: Dang
authors: Huijun
authors: H
authors: Yang
authors: Shaojun
authors: S
authors: Zhu
authors: Jun
authors: J
authors: Kohyama
authors: Issay
authors: I
authors: Kitabayashi
authors: Webster K
authors: WK
authors: Cavenee
authors: Timothy F
authors: TF
authors: Cloughesy
authors: Frank B
authors: FB
authors: Furnari
authors: Masaya
authors: M
authors: Nakamura
authors: Yoshiaki
authors: Y
authors: Toyama
authors: Hideyuki
authors: H
authors: Okano
authors: Paul S
authors: PS
authors: Mischel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D000077237:Arsenic Trioxide