Abstract A051 Genome-wide CRISPR/Cas9 library screening identified TP53 as a critical driver for resistance to EZH2 inhibitor in rhabdoid tumors

Abstract Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies which occur in kidney, soft-parts and brain. They are characterized by a complete inactivation of the SMARCB1 tumor suppressor gene encoding a core subunit of the chromatin remodeling SWI/SNF complex. Prognosis for children with RTs is poor as, in many instances, these tumors are resistant to conventional type chemotherapy. Pharmacological inhibition of EZH2 is a promising strategy to treat some tumors with loss of function in SMARCB1. However, the clinical response rate remains low, and both primary and secondary resistance have been reported. Understanding the mechanisms of resistance to EZH2 inhibition may allow new therapeutic hypothesis. For this purpose, we realized a genome-wide CRISPR-Cas9 knockout screening on two rhabdoid cell lines treated with EZH2 inhibitor. We identified TP53 loss as the sole consistent gene knock-out able to confer some resistance to EZH2 inhibition in both cell lines. Conversely, we demonstrated that MDM2/MDM4 inhibition, in a TP53-dependant manner, strongly synergized with EZH2 inhibition to control cell lines viability in vitro. We further treated 4 rhabdoid patient-derived xenografts with UNC1999, Idasanutlin and the combination of both and observed a potent tumor growth control upon combined EZH2 and MDM2/MDM4 inhibitions. To conclude, our results strongly encourage to assess the actual efficacy of combined MDM2/MDM4 and EZH2 inhibitors in the treatment of patients with SMARCB1-deficient rhabdoid tumors. Citation Format: Céline Chauvin, Tiphaine Hery, Rachida Bouarich, Fariba Nemati, Diego Teyssonneau, Camille Fouassier, Chiara Giudiceandrea, Zhi-Yan Han, Sakina Zaidi, Didier Surdez, Sergio Roman-Roman, Didier Decaudin, Raphaël Margueron, Franck Bourdeaut. Genome-wide CRISPR/Cas9 library screening identified TP53 as a critical driver for resistance to EZH2 inhibitor in rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A051.