title: mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.
abstract: High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.
authors.affiliation: Labratory of Medical Genetics, Harbin Medical University, 157 Baojian Rd, Nangang Dist, Harbin, 150081, Heilongjiang, China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Dou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Shan
authors.initials: S
authors.lastname: Guan
authors.forename: Zhenghu
authors.initials: Z
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: shi
authors.forename: Roma
authors.initials: R
authors.lastname: Patel
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Vasudevan
authors.forename: Peter E
authors.initials: PE
authors.lastname: Zage
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jed G
authors.initials: JG
authors.lastname: Nuchtern
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D064593:Heterografts; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000255:Adenosine Triphosphate; D000903:Antibiotics, Antineoplastic; D001583:Benzoxazoles; D004317:Doxorubicin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine