Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor

Abstract

Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of cell line panels to identify a heightened sensitivity of rhabdoid tumor to mithramycin and the second‐generation analogue EC8042. The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1‐deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM‐defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3‐day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice.

The Genes–Stemness–Secretome Interplay in Malignant Pleural Mesothelioma: Molecular Dynamics and Clinical Hints

“…Notably, merlin is known to be critical for maintaining normal structure and function of the hematopoietic stem cell niche [ 132 ], and FAK cooperates in preserving the self-renewal of CSC, and the overexpression of merlin has been shown to affect proliferation and viability of CSC-enriched MPM [ 133 ]. Mithramycin is an antineoplastic agent produced by Streptomyces plicatus which behaves as DNA/RNA polymerase inhibitor, DNA-binding transcriptional inhibitor and antibiotic and has been observed to facilitate tumor necrosis factor (TNF)-α activity and Fas-ligand-induced, which is known to induce malignant cell reprogramming, differentiation, and senescence [ 134 , 135 ]. The NCT02859415 is a phase I/II trial aimed at evaluating continuous 24h intravenous infusion of mithramycin in patients with thoracic malignancies, including MPM.…”

SMARCB1-Deficient Cancers: Novel Molecular Insights and Therapeutic Vulnerabilities

“…While there are no current methods to restore SMARCB1 function in tumors, this mechanism offers a way to mimic the effects of SMARCB1 reconstitution. Further studies are needed to validate these mechanisms, but current studies offer promising new insights that may be used for future therapeutics [ 30 ].…”

Importance of pharmacologic considerations in the development of targeted anticancer agents for children

“…One 53]. Although there is one example of directly targeting the residual mutated SWI/SNF complex with EC-8042 (AIT102) [54], the majority of the work has focused on the antagonism that is lost with the PRC2 complex and EZH2 [55][56][57] ]. The schedule used in this study was 800 mg given twice daily by mouth continuously for 28 days.…”

“…RT has a somatic mutation frequency among the lowest in human cancer [2 ▪▪ ], with one clear oncogenic driver, a deletion in SMARCB1 (or less commonly SMARCA4) of the chromatin remodeling complex SWI/SNF [52 ▪ ,53]. Although there is one example of directly targeting the residual mutated SWI/SNF complex with EC-8042 (AIT102) [54], the majority of the work has focused on the antagonism that is lost with the PRC2 complex and EZH2 [55–57]. The SMARCB1 negative ES has led to tazemetostat's approval for this indication based on an objective response rate of 15% (95% Confidence Interval [CI] 7 to 26) and a 26% (95% CI 16 to 39) disease control rate at 32 weeks [58 ▪▪ ].…”