A synergistic interaction between HDAC- and PARP inhibitors in childhood tumors with chromothripsis

Expression data of medulloblastoma patient derived xenograft spheroids upon BGB 290 and romidepsin treatment alone and in combination: Romidepsin and BGB 290 shows synergistic growth inhibition in medulloblastoma patient derived xenograft spheroid models in vitro and in vivo. Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses, and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment. We used microarrays to detail the differential gene expression upon BGB 290 and romidepsin treatment either alone and in combination to determine the underlying cause of synergistic interaction between the two anticancer drugs. Cells from 3 Sonic Hedgehog medulloblastoma patient derived xenograft spheroid models (LFS_MB_P, primary tumor, LFS_MB_1R, first relapse and RCMB18) were treated with either vehicle control, BGB 290 (IC20), romidepsin (IC20) or BGB 290 (IC20) with romidepsin (IC20) for 24 hours. Pictures were taken using a bright-field microscope to determine the effect of the treatment on the spheroid growth. RNA was then isolated and expression data were generated using Affymetrix Clariom S arrays. Copy number states from EPIC and 450K methylation arrays were assessed by the Bioconductor package conumee. 11 samples were profiled on IlluminaHumanMethylation850k arrays