Aurora A Kinase Inhibition Is Synthetic Lethal With the Activation of MYCN in Retinoblastoma

RB1 inactivation and MYCN activation have been documented as common oncogenic alterations in retinoblastoma (RB). Direct targeting of RB1 and MYCN has not yet been proven to be feasible. The current treatment options for RB mainly consist of conventional chemotherapy, which inevitably poses health-threatening side effects. Here, we aimed to screen an in-house compound library to identify potential drugs for the treatment of human RB.

Aurora A kinase (AURKA) inhibitors were identified by differential viability screening with a tool compound library, and the pharmacological safety and efficacy of candidate drugs were further validated in zebrafish and RB patient-derived xenograft (PDX) models in vivo. Further CUT & Tag assay, ChIP-qPCR and RNA seq performances showed that MYCN binds to the AURKA promoter and upregulates its transcription, suggesting that AURKA inhibition induces synthetic lethality in RB.

In this study, we revealed that AURKA inhibitors exhibited high therapeutic efficacy against RB both in vitro and in vivo. Mechanistically, we found that MYCN could bind to the AURKA promoter region to regulate its transcription, thereby promoting AURKA expression and consequently driving RB progression. Interestingly, AURKA inhibition exhibited synthetic lethality with RB1-deficient and MYCN-amplification in RB cells.

Collectively, these findings demonstrate that AURKA is crucial for RB progression and further expanded the current understanding of synthetic lethal therapeutic strategies. Our study indicates that AURKA inhibitors may represent a new therapeutic strategy for selectively targeting patients with RB with RB1-deficient and MYCN-amplification to improve the prognosis of aggressive types of patients with RB.