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

International Journal of Cancer. Journal International Du Cancer
Irina AlimovaRajeev Vibhakar

Abstract

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 BE...Continue Reading

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Citations

Mar 5, 2020·Neuro-oncology·Lindsey M HoffmanAnnie Huang
Apr 1, 2020·Neuro-oncology·Charles G Eberhart, Jeffrey A Rubens
Apr 19, 2020·Nature Reviews. Clinical Oncology·Priya Mittal, Charles W M Roberts
Apr 9, 2020·Cells·Daniel Massó-Vallés, Laura Soucek
May 3, 2019·Nature Communications·April M WeissmillerWilliam P Tansey
Jul 14, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sabrina Z WangJeffrey A Rubens
Feb 16, 2021·Frontiers in Oncology·Anna BorgenvikFredrik J Swartling
Jun 24, 2021·The Journal of Cell Biology·Jonathan R Whitfield, Laura Soucek

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