RB1 loss triggers dependence on ESRRG in retinoblastoma

Menée à partir de l'analyse de l'exome et du génome d'échantillons tumoraux issus de patients atteints d'un rétinoblastome, cette étude démontre que la perte de l'expression du suppresseur de tumeur RB1 déclenche la dépendance des cellules cancéreuses au récepteur ESRRG

Résumé en anglais

Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death, which is exacerbated in hypoxia. These findings reveal a previously unidentified dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb. ESRRG as an essential mediator of hypoxic adaptation and cell survival in retinoblastoma offers a promising therapeutic target.