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Preferential sensitivity to HDAC inhibitors in tumors with CREBBP mutation


Mutations in the gene encoding for the histone acetyltransferase (HAT) CREBBP are common driver events in multiple types of human cancer, such as small cell lung cancer (SCLC) or Sonic Hedgehog medulloblastoma (SHH MB). Therefore, therapeutic options targeting such alterations are highly desired. We used human cell lines from SCLC as well as primary mouse tumor cells and genetically engineered mouse models for SHH MB to test treatment options with histone deacetylase inhibitors (HDACi) in CREBBP wild-type and mutated tumors. In contrast to CREBBP wild-type SCLC cells, CREBBP-mutated SCLC cells showed significantly lower IC50 values after treatment with HDACi. In addition, both in vitro and in vivo, HDACi had significant effects on cell proliferation of SHH-driven tumor MB cells harboring a CREBBP-mutation as compared to CREBBP wild-type controls. These data suggest that HDACi may serve as an additional therapeutic option for patients suffering from tumors driven by CREBBP mutations.

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  1. 1.

    Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488:100–5.

  2. 2.

    Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, et al. The whole-genome landscape of medulloblastoma subtypes. Nature. 2017;547:311–7.

  3. 3.

    Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393–405.

  4. 4.

    Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104–10.

  5. 5.

    Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011;471:235–9.

  6. 6.

    Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95.

  7. 7.

    Taylor MD, Mainprize TG, Rutka JT, Becker L, Bayani J, Drake JM. Medulloblastoma in a child with Rubenstein-Taybi Syndrome: case report and review of the literature. Pedia Neurosurg. 2001;35:235–8.

  8. 8.

    Miller RW, Rubinstein JH. Tumors in Rubinstein-Taybi syndrome. Am J Med Genet. 1995;56:112–5.

  9. 9.

    Merk DJ, Ohli J, Merk ND, Thatikonda V, Morrissy S, Schoof M, et al. Opposing effects of CREBBP mutations govern the phenotype of Rubinstein-Taybi syndrome and adult SHH medulloblastoma. Dev Cell. 2018;44:709–.e706.

  10. 10.

    Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D, et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 2006;66:10171–8.

  11. 11.

    Machold R, Fishell G. Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron. 2005;48:17–24.

  12. 12.

    Zhang Z, Hofmann C, Casanova E, Schutz G, Lutz B. Generation of a conditional allele of the CBP gene in mouse. Genesis. 2004;40:82–89.

  13. 13.

    Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990;265:17174–9.

  14. 14.

    Pei Y, Liu KW, Wang J, Garancher A, Tao R, Esparza LA, et al. HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell. 2016;29:311–23.

  15. 15.

    Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell. 2008;14:123–34.

  16. 16.

    Karpova NN. Role of BDNF epigenetics in activity-dependent neuronal plasticity. Neuropharmacology. 2014;76(Pt C):709–18.

  17. 17.

    Koppel I, Timmusk T. Differential regulation of Bdnf expression in cortical neurons by class-selective histone deacetylase inhibitors. Neuropharmacology. 2013;75:106–15.

  18. 18.

    Wu X, Chen PS, Dallas S, Wilson B, Block ML, Wang CC, et al. Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol. 2008;11:1123–34.

  19. 19.

    Jia D, Augert A, Kim DW, Eastwood E, Wu N, Ibrahim AH, et al. Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition. Cancer Discov. 2018;8:1422–37.

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We are indebted to Michael Schmidt, Silvia Occhionero, Marie-Christin Burmester. and Veronika Kaltenbrunn for excellent technical support.


This work was supported by grants from the German Cancer Aid, the Wilhelm-Sander Stiftung, and the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg.

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Correspondence to Ulrich Schüller.

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