NFκB signaling in alveolar rhabdomyosarcoma

Megan M. Cleary, Atiya Mansoor, Teagan Settelmeyer, Yuichi Ijiri, Katherine J. Ladner, Matthew N. Svalina, Brian P. Rubin, Denis C. Guttridge, Charles Keller

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB-YY1-miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways. We found that pharmacological inhibition of NFκB activity resulted in decreased cell proliferation of many of the aRMS tumor cultures. Surprisingly, mice that were orthotopically allografted with aRMS tumor cells exhibited no difference in tumor growth when administered an NFκB inhibitor, compared to control. Furthermore, inhibition of NFκB by genetically ablating its activating kinase inhibitor, IKKβ, by conditional deletion in a mouse model harboring the Pax3:Foxo1 chimeric oncogene failed to abrogate spontaneous tumor growth. Genetically engineered mice with conditionally deleted IKKβ exhibited a paradoxical decrease in tumor latency compared with those with active NFκB. However, using a synthetic-lethal approach, primary cell cultures derived from tumors with inactivated NFκB showed sensitivity to the BCL-2 inhibitor navitoclax. When used in combination with an NFκB inhibitor, navitoclax was synergistic in decreasing the growth of both human and IKKβ wild-type mouse aRMS cells, indicating that inactivation of NFκB alone may not be sufficient for reducing tumor growth, but, when combined with another targeted therapeutic, may be clinically beneficial.

Original languageEnglish (US)
Pages (from-to)1109-1115
Number of pages7
JournalDMM Disease Models and Mechanisms
Volume10
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

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Keywords

  • Cancer
  • IKKβ
  • NFκB
  • Rhabdomyosarcoma

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cleary, M. M., Mansoor, A., Settelmeyer, T., Ijiri, Y., Ladner, K. J., Svalina, M. N., ... Keller, C. (2017). NFκB signaling in alveolar rhabdomyosarcoma. DMM Disease Models and Mechanisms, 10(9), 1109-1115. https://doi.org/10.1242/dmm.030882