title: Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target.
abstract: Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Melanie F
authors: MF
authors: Weingart
authors: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Jacquelyn J
authors: JJ
authors: Roth
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Marianne
authors: M
authors: Hutt-Cabezas
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Tracy M
authors: TM
authors: Busse
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Harpreet
authors: H
authors: Kaur
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Antoinette
authors: A
authors: Price
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Rachael
authors: R
authors: Maynard
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Jeffrey
authors: J
authors: Rubens
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Isabella
authors: I
authors: Taylor
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Xing-Gang
authors: XG
authors: Mao
authors: Division of Hematology, Oncology, and Blood & Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Jingying
authors: J
authors: Xu
authors: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors: Yasumichi
authors: Y
authors: Kuwahara
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Sariah J
authors: SJ
authors: Allen
authors: Division of Hematology, Oncology, and Blood & Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.|The Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors: Anat
authors: A
authors: Erdreich-Epstein
authors: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors: Bernard E
authors: BE
authors: Weissman
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Brent A
authors: BA
authors: Orr
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Charles G
authors: CG
authors: Eberhart
authors: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors: Jaclyn A
authors: JA
authors: Biegel
authors: Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.|Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA.
authors: Eric H
authors: EH
authors: Raabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D013724:Teratoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C516326:LIN28B protein, human; C000715187:Lin28A protein, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras)
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