A synergistic interaction between HDAC‐ and PARP inhibitors in childhood tumors with chromothripsis
Umar Khalid, Milena Simović, Linda Hammann, Murat Iskar, John Wong, Rithu Kumar, Manfred Jugold, Martin Sill, Michiel Bolkestein, Thorsten Kolb, Michaela Hergt, Frauke Devens, Jonas Ecker, Marcel Kool, Till Milde, Frank Westermann, Axel Benner, Joe Lewis, Sascha Dietrich, Stefan M. Pfister, Peter Lichter, Marc Zapatka, Aurélie Ernst
Abstract
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.