In gratitude of the loyal support of our members, the CNS is offering complimentary 2021 Annual Meeting registration to all members! Learn more.

  • Genome-wide shRNA Screening Defines the SUMO-activating Enzyme (SAE1/2) as a Novel Therapeutic Target for Tumors Driven by c-Myc Oncogenesis

    Final Number:
    112

    Authors:
    J.D. Kessler; Kristopher Thomas Kahle MD PhD; T. Sun; K.L. Meerbrey; M.R. Schlabach; E.M. Schmitt; S.O. Skinner; Q. Xu; M.Z. Li; Z.C. Hartman; M. Rao; P. Yu; R. Dominguez-Vidana; A.C. Liang; N.L. Solimini; R.J. Bernardi; J. Yu; T. Hsu; I. Golding; J. Luo; C.K. Osborne; C.J. Creighton; S.G. Hilsenbeck; R. Schiff; C.A. Shaw; S.J. Elledge; Thomas Westbrook

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2012 Annual Meeting

    Introduction: The c-MYC oncogene is a pivotal regulator of tumorigenesis in many human cancers, and is often associated with particularly aggressive tumors in breast cancer and medulloblastoma. c-Myc has proven difficult to target pharmacologically, highlighting the need for alternative therapeutic approaches. We exploited the principle of “non-oncogene addiction” to identify genes required by c-Myc for the maintenance of its tumorigenic phenotype in order to define novel drug targets.

    Methods: We performed an RNAi genome-wide screen looking for c-Myc-synthetic lethal shRNAs (using a library of 74,905 total shRNAs targeting 32,293 unique transcripts) in the HMEC human epithelial cancer cell engineered with an inducible a c-Myc-estrogen receptor fusion transgene. Top-scoring shRNAs lethal to cells with overexpressed c-Myc but not in cells without c-Myc overexpression were validated in vitro with cell proliferation assays and in mice with implantable c-Myc-dependent tumors. Gene expression data for nearly 1,300 tumors from patients harboring c-Myc-dependent tumors was stratified according to whether their tumor c-Myc activity was high or low, and associations between lethal genes and c-Myc status was assessed.

    Results: We uncovered a novel role for the SUMO-activating enzyme (SAE1/2) in the maintenance of the c-Myc oncogenic phenotype. Inactivation of SAE1/2 drives synthetic lethality with c-Myc to promote mitotic catastrophe and cell death selectively in cancer cells but not normal cells. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of c-Myc from activated to repressed. A subset of these genes are required for mitotic spindle function and to support the c-Myc tumorigenesis. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients.

    Conclusions: Inhibition of SAE1/2 merits investigation as a novel therapy for Myc-driven human cancers, such as breast cancer and medulloblastoma.

    Patient Care: We have identified a gene selectively lethal to human cancer cells driven by c-Myc, one of the most common and deadly oncogenes. This is a potential drug target for patients with tumors in which c-Myc plays a critical role, like aggressive subtypes of medulloblastoma.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of the c-Myc ongene for tumorigenesis, especially in medulloblastoma. 2) Discuss, in small groups, exciting new approaches for drug discovery using genome-wide siRNA technology, and how these techniques could be used for multiple brain tumor types 3) Identify a potentially novel target for tumors driven by c-Myc oncogenesis

    References: Recently published as: Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, Rao M, Yu P, Dominguez-Vidana R, Liang AC, Solimini NL, Bernardi RJ, Yu B, Hsu T, Golding I, Luo J, Osborne CK, Creighton CJ, Hilsenbeck SG, Schiff R, Shaw CA, Elledge SJ, Westbrook TF. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2012 Jan 20;335(6066):348-53. Featured in: 1. http://www.focushms.com/features/new-target-found-for-aggressive-cancer-gene/ 2. Evan G. Cancer. Taking a back door to target Myc. Science. 2012 Jan 20;335(6066):293-4. No abstract available.

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy