Inhibition of MYC attenuates tumor cell self-renewal and promotes senescence in SMARCB1-deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo

Irina Alimova, Angela Pierce, Etienne Danis, Andrew Donson, Diane K. Birks, Andrea Griesinger, Nicholas K. Foreman, Mariarita Santi, Laura Soucek, Sujatha Venkataraman, Rajeev Vibhakar

Research output: Contribution to journalArticleResearch

12 Citations (Scopus)

Abstract

© 2018 UICC Loss of SMARCB1 is the hallmark genetic event that characterizes rhabdoid tumors in children. Rhabdoid tumors of the brain (ATRT) occur in young children and are particularly challenging with poor long-term survival. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. Recent studies demonstrate that ATRT consists of 3 genomic subgroups with a subset of poor outcome tumors expressing high BMP and MYC pathway activation. Here we show that MYC occupies distinct promoter loci in ATRT compared to embryonic stem (ES) cells. Furthermore, using human ATRT cell lines, patient-derived cell culture, ex vivo patient-derived tumor, and orthotopic xenograft models, we show that MYC inhibition is a molecular vulnerability in SMARCB1-deleted tumors and that such inhibition effectively suppresses BMP and pluripotency-associated genomic programs, attenuates tumor cell self-renewal, promotes senescence, and inhibits ATRT tumor growth in vivo. Transgenic expression of Omomyc (a bona-fide MYC dominant negative) or chemical inhibition of MYC transcriptomic programs with the BET inhibitor JQ1 phenocopy genetic depletion of MYC, effectively restricting ATRT tumor growth and opening a promising therapeutic avenue for rhabdoid tumors in children.
Original languageEnglish
Pages (from-to)1983-1995
JournalInternational Journal of Cancer
Volume144
DOIs
Publication statusPublished - 15 Apr 2019

Keywords

  • ATRT
  • MYC
  • rhabdoid tumor
  • SMARCB1
  • SWI/SNF complex

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