In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3091-3091
Abstract:
Myc is an oncogenic transcription factor frequently dysregulated in human malignancies. While the transcriptional programs and other functions of Myc have been intensively studied, there remains no effective strategy for inhibiting Myc in patients. To search for pathways that support the Myc oncogenic program, we employed a next-generation RNAi screen for Myc-synthetic lethal (MySL) genes. Using this strategy, we have identified several cellular processes required to tolerate oncogenic Myc. Key among these is the core sumoylation machinery, and we define the Sumo-activating enzyme (SAE) as a central component in this MySL network. Loss of SAE drives synthetic lethality with Myc, and the enzymatic activity of SAE is required to support the Myc oncogenic state. Inactivation of SAE leads to mitotic catastrophe and cell death selectively upon Myc hyper-activation. Mechanistically, depletion of SAE switches a subprogram of Myc transcriptional targets governing mitotic spindle function from activated to repressed, a subprogram we term Sumoylation-dependent Myc Switchers, or SMS genes. Notably, SMS genes are required to tolerate Myc hyper-activation, and SAE and the SMS program are required for Myc-dependent breast cancer cell survival in vitro and tumor growth and progression in vivo. Importantly, patient survival significantly correlates with levels of SAE and SMS gene expression in Myc-high tumors. Collectively, these studies reveal a mitotic vulnerability of Myc-driven cancers and demonstrate that inhibiting sumoylation can selectively impair mitosis and survival in an oncogenic Myc-dependent manner. We propose that drugs targeting SAE and its downstream SMS targets may have therapeutic benefits for patients with Myc-driven cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3091. doi:1538-7445.AM2012-3091
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-3091
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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