| First Author | Cleary MM | Year | 2017 |
| Journal | Dis Model Mech | Volume | 10 |
| Issue | 9 | Pages | 1109-1115 |
| PubMed ID | 28883017 | Mgi Jnum | J:244026 |
| Mgi Id | MGI:5912805 | Doi | 10.1242/dmm.030882 |
| Citation | Cleary MM, et al. (2017) NFkappaB signaling in alveolar rhabdomyosarcoma. Dis Model Mech 10(9):1109-1115 |
| abstractText | 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 NFkappaB-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 NFkappaB 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 NFkappaB 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 NFkappaB inhibitor, compared to control. Furthermore, inhibition of NFkappaB by genetically ablating its activating kinase inhibitor, IKKbeta, 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 IKKbeta exhibited a paradoxical decrease in tumor latency compared with those with active NFkappaB. However, using a synthetic-lethal approach, primary cell cultures derived from tumors with inactivated NFkappaB showed sensitivity to the BCL-2 inhibitor navitoclax. When used in combination with an NFkappaB inhibitor, navitoclax was synergistic in decreasing the growth of both human and IKKbeta wild-type mouse aRMS cells, indicating that inactivation of NFkappaB alone may not be sufficient for reducing tumor growth, but, when combined with another targeted therapeutic, may be clinically beneficial. |
