Post-translational modifications by the small ubiquitin-like modifier (SUMO) family are important in oncogenesis and cellular response to DNA damage. Recent findings indicate that the key oncogenic pathways driven by Myc and KRas are dependent on, or addicted to, SUMOylation. In one study, genome-wide siRNA knockdown identified the gene encoding the catalytic subunit of the SUMO activating enzyme (SAE), SAE2, as having the strongest synthetic lethal interaction with Myc hyperactivation. Similarly, genes encoding the SUMOylation enzymes were found to be critical for KRas-dependent tumorigenesis. Based on these findings, we hypothesize that the SAE is a novel target for developing anti-cancer therapeutics for cancers that are Myc-and KRas-dependent. The over-arching goal of this proposal is to test this hypothesis, and the proposed studies are enabled by our discovery of potent and specific SAE inhibitors that have selective toxicity to cancer cell lines that have high Myc-expression levels and/or KRas mutation. We propose to investigate the molecular mechanisms underlying the synthetic lethality of SUMOylation with Myc hyperactivation and KRas mutations in order to further validate the SAE as a potential cancer therapeutic target. In addition, we will investigate the structure-activity relationship of how the inhibitors interact with the SAE and inhibit its enzymatic activity, and use this information to guide further improvement of the inhibitors. These studies could potentially improve treatment of many cancers, as overexpression of Myc is estimated to contribute to 70% of all human cancers, and KRas is also frequently mutated in human cancers. However, both Myc and KRas have proven difficult to inhibit pharmacologically. Thus, the proposed studies will likely establis a new paradigm to target the SAE for the development of novel cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM086171-06S1
Application #
8754756
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Willis, Kristine Amalee
Project Start
2008-04-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Jiang, Xi; Hu, Chao; Ferchen, Kyle et al. (2018) Author Correction: Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun 9:670
Ambaye, Nigus; Chen, Chih-Hong; Khanna, Swati et al. (2018) Streptonigrin Inhibits SENP1 and Reduces the Protein Level of Hypoxia-Inducible Factor 1? (HIF1?) in Cells. Biochemistry 57:1807-1813
Yan, Wei; Wu, Xiwei; Zhou, Weiying et al. (2018) Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol 20:597-609
Lv, Zongyang; Yuan, Lingmin; Atkison, James H et al. (2018) Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme. Nat Commun 9:5145
Lv, Zongyang; Yuan, Lingmin; Atkison, James H et al. (2017) Domain alternation and active site remodeling are conserved structural features of ubiquitin E1. J Biol Chem 292:12089-12099
Cho, May; Gong, Jun; Frankel, Paul et al. (2017) A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. Oncotarget 8:79750-79760
Kuo, Ching-Ying; Cheng, Chun-Ting; Hou, Peifeng et al. (2016) HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. Oncotarget 7:34052-69
Du, Li; Li, Yi-Jia; Fakih, Marwan et al. (2016) Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal. Nat Commun 7:12326
Yue, Peibin; Lopez-Tapia, Francisco; Paladino, David et al. (2016) Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo. Cancer Res 76:652-63
Alontaga, Aileen Y; Ambaye, Nigus D; Li, Yi-Jia et al. (2016) Observation of an E2 (Ubc9)-homodimer by crystallography. Data Brief 7:195-200

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