Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target
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Melanie F. Weingart1, Jacquelyn J. Roth7, Marianne Hutt-Cabezas1, Tracy M. Busse8, Harpreet Kaur1, Antoinette Price1, Rachael Maynard1, Jeffrey Rubens1, Isabella Taylor1, Xing-gang Mao1, Jingying Xu4, Yasumichi Kuwahara3, Sariah J. Allen6, Anat Erdreich-Epstein4,5, Bernard E. Weissman3, Brent A. Orr6, Charles G. Eberhart1, Jaclyn A. Biegel7,8,9 and Eric H. Raabe1,2
1 Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
2 Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA
3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
4 Division of Hematology, Oncology, and Blood & Bone Marrow Transplant, Children’s Hospital Los Angeles, Los Angeles, CA, USA
5 The Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
6 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
7 Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
8 Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
9 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Eric H. Raabe, email:
Keywords: ERK, AZD6244, let-7, RAS, LIN28, malignant rhabdoid tumor
Received: December 18, 2014 Accepted: December 22, 2014 Published: December 26, 2014
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.
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