Mutations in UBA3 Confer Resistance to the NEDD8-Activating Enzyme Inhibitor MLN4924 in Human Leukemic Cells
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Author
Xu, G. Wei
Toth, Julia I.
da Silva, Sara R.
Paiva, Stacey-Lynn
Lukkarila, Julie L.
Hurren, Rose
Maclean, Neil
Sukhai, Mahadeo A.
Bhattacharjee, Rabindra N.
Goard, Carolyn A.
Gunning, Patrick T.
Dhe-Paganon, Sirano
Petroski, Matthew D.
Schimmer, Aaron D.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1371/journal.pone.0093530Metadata
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Xu, G. W., J. I. Toth, S. R. da Silva, S. Paiva, J. L. Lukkarila, R. Hurren, N. Maclean, et al. 2014. “Mutations in UBA3 Confer Resistance to the NEDD8-Activating Enzyme Inhibitor MLN4924 in Human Leukemic Cells.” PLoS ONE 9 (4): e93530. doi:10.1371/journal.pone.0093530. http://dx.doi.org/10.1371/journal.pone.0093530.Abstract
The NEDD8-activating enzyme (NAE) initiates neddylation, the cascade of post-translational NEDD8 conjugation onto target proteins. MLN4924, a selective NAE inhibitor, has displayed preclinical anti-tumor activity in vitro and in vivo, and promising clinical activity has been reported in patients with refractory hematologic malignancies. Here, we sought to understand the mechanisms of resistance to MLN4924. K562 and U937 leukemia cells were exposed over a 6 month period to MLN4924 and populations of resistant cells (R-K562MLN, R-U937MLN) were selected. R-K562MLN and R-U937MLN cells contain I310N and Y352H mutations in the NAE catalytic subunit UBA3, respectively. Biochemical analyses indicate that these mutations increase the enzyme’s affinity for ATP while decreasing its affinity for NEDD8. These mutations effectively contribute to decreased MLN4924 potency in vitro while providing for sufficient NAE function for leukemia cell survival. Finally, R-K562MLN cells showed cross-resistance to other NAE-selective inhibitors, but remained sensitive to a pan-E1 (activating enzyme) inhibitor. Thus, our work provides insight into mechanisms of MLN4924 resistance to facilitate the development of more effective second-generation NAE inhibitors.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972249/pdf/Terms of Use
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