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Comprehensive quantitative proteomic profiling of the pharmacodynamic changes induced by MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with azacitidine

Leukemia volume 30, pages 1190–1194 (2016)Cite this article

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NEDDylation controls the ubiquitination and proteasomal degradation of proteins that are critical for cell survival, oncogenic transformation and therapeutic sensitivity, including p27, CDT1, IκBα, NRF-2, cyclin E, c-Myc, p53 and hypoxia-inducible factor-1α.1 Aberrant NEDDylation has been implicated in malignant pathogenesis and drug resistance, thus providing strong rationale to develop strategies to disrupt this specific mechanism of protein turnover for cancer therapy. MLN4924 (Pevonedistat) is a first-in-class inhibitor of NEDDylation that has been evaluated in multiple phase I trials.2 Despite its robust effects in preclinical models of acute myeloid leukemia (AML) and preliminary efficacy in patients with relapsed/refractory AML and high-risk myelodysplastic syndromes (MDS), the specific pharmacodynamic effects that mediate the antileukemic activity of MLN4924 have not been completely defined and no predictive biomarkers of clinical sensitivity to MLN4924 have been validated.3, 4, 5

Reactome network analysis of the 47 top proteins whose levels were increased two or more fold by MLN4924 treatment demonstrated that the affected proteins primarily clustered in the cell cycle, mitosis and stress response pathways (Supplementary Table S1). We also merged our proteomic profiling of MV4-11 AML cells with a comprehensive SILAC analysis performed in A375 melanoma cells similarly treated with MLN4924. We determined that 36% (17/47) of the proteins that were pharmacodynamically increased by MLN4924 were identical between the two analyses.9 The proteins that differed between these two studies are detailed in Supplementary Table S2. Considering that the majority (nearly two-thirds) of the proteins that were modulated by drug treatment were distinct in this analysis, the repertoire of proteins that are modulated by this agent may be tumor-type dependent.7, 9 It is possible that the spectrum of affected targets in individual tumors may be important in determining sensitivity to MLN4924 as patients with MDS/AML have responded better to this agent than those with other malignancies based on initial phase I studies.2

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Acknowledgements

This work was supported by the National Cancer Institute grant R01CA172443 (to JSC).

Author contributions

VV analyzed and interpreted data and wrote the manuscript; STN analyzed and interpreted data and participated in manuscript preparation; CME performed experiments, analyzed the data, and edited the manuscript; KRK provided intellectual input and contributed to manuscript preparation; AP and SAB performed proteome profiling and contributed to manuscript preparation; YH participated in manuscript preparation; HEC, AN, ASA, JPM and MAS contributed to data interpretation and manuscript preparation; JSC designed the study, analyzed and interpreted data and wrote the manuscript. All authors approved the manuscript before submission.

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Author notes

  1. V Visconte and S T Nawrocki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    V Visconte, Y Han, J P Maciejewski, M A Sekeres & J S Carew

  2. Division of Hematology/Oncology, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    S T Nawrocki & C M Espitia

  3. USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    K R Kelly

  4. Cell Signaling Technology, Danvers, MA, USA

    A Possemato & S A Beausoleil

  5. Department of Hematology/Oncology, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    H E Carraway, A Nazha, A S Advani & M A Sekeres

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  1. V Visconte
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Corresponding author

Correspondence to J S Carew.

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Competing interests

AP and SAB are employees of Cell Signaling Technology. The other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Visconte, V., Nawrocki, S., Espitia, C. et al. Comprehensive quantitative proteomic profiling of the pharmacodynamic changes induced by MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with azacitidine. Leukemia 30, 1190–1194 (2016). https://doi.org/10.1038/leu.2015.250

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