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: 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 5 Pg. 3165-77 (Feb 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25638158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• KRAS protein, human
• LIN28B protein, human
• Lin28A protein, human
• MicroRNAs
• Protein Kinase Inhibitors
• RNA-Binding Proteins
• mirnlet7 microRNA, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Brain Neoplasms (drug therapy, enzymology, genetics)
• Cell Line, Tumor
• Cell Proliferation
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• MicroRNAs (genetics, metabolism)
• Molecular Targeted Therapy
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• RNA Interference
• RNA-Binding Proteins (genetics, metabolism)
• Rhabdoid Tumor (drug therapy, enzymology, genetics)
• Teratoma (drug therapy, enzymology, genetics)
• Time Factors
• Transfection
• Tumor Burden
• Xenograft Model Antitumor Assays