Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target

Melanie F. Weingart, Jacquelyn J. Roth, Marianne Hutt-Cabezas, Tracy M. Busse, Harpreet Kaur, Antoinette Price, Rachael Maynard, Jeffrey Rubens, Isabella Taylor, Xing gang Mao, Jingying Xu, Yasumichi Kuwahara, Sariah J. Allen, Anat Erdreich-Epstein, Bernard E. Weissman, Brent A. Orr, Charles G. Eberhart, Jaclyn A. Biegel, Eric H. Raabe

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3165-3177
Number of pages13
JournalOncotarget
Volume6
Issue number5
DOIs
StatePublished - 2015

Keywords

  • AZD6244
  • ERK
  • LIN28
  • Let-7
  • Malignant rhabdoid tumor
  • RAS

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Weingart, M. F., Roth, J. J., Hutt-Cabezas, M., Busse, T. M., Kaur, H., Price, A., Maynard, R., Rubens, J., Taylor, I., Mao, X. G., Xu, J., Kuwahara, Y., Allen, S. J., Erdreich-Epstein, A., Weissman, B. E., Orr, B. A., Eberhart, C. G., Biegel, J. A., & Raabe, E. H. (2015). Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget, 6(5), 3165-3177. https://doi.org/10.18632/oncotarget.3078