Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase

Uffe H Olesen, Jakob G Petersen, Antje Garten, Wieland Kiess, Jun Yoshino, Shin-Ichiro Imai, Mette K Christensen, Peter Fristrup, Annemette V Thougaard, Fredrik Björkling, Peter B Jensen, Søren J Nielsen, Maxwell Sehested

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BACKGROUND: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) are promising cancer drugs currently in clinical trials in oncology, including APO866, CHS-828 and the CHS-828 prodrug EB1627/GMX1777, but cancer cell resistance to these drugs has not been studied in detail. METHODS: Here, we introduce an analogue of CHS-828 called TP201565 with increased potency in cellular assays. Further, we describe and characterize a panel of cell lines with acquired stable resistance towards several NAMPT inhibitors of 18 to 20,000 fold compared to their parental cell lines. RESULTS: We find that 4 out of 5 of the resistant sublines display mutations of NAMPT located in the vicinity of the active site or in the dimer interface of NAMPT. Furthermore, we show that these mutations are responsible for the resistance observed. All the resistant cell lines formed xenograft tumours in vivo. Also, we confirm CHS-828 and TP201565 as competitive inhibitors of NAMPT through docking studies and by NAMPT precipitation from cellular lysate by an analogue of TP201565 linked to sepharose. The NAMPT precipitation could be inhibited by addition of APO866. CONCLUSION: We found that CHS-828 and TP201565 are competitive inhibitors of NAMPT and that acquired resistance towards NAMPT inhibitors can be expected primarily to be caused by mutations in NAMPT.
Original languageEnglish
JournalB M C Cancer
Issue number1
Pages (from-to)677
Publication statusPublished - 2010

Bibliographical note

© 2010 Olesen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Olesen, U. H., Petersen, J. G., Garten, A., Kiess, W., Yoshino, J., Imai, S-I., Christensen, M. K., Fristrup, P., Thougaard, A. V., Björkling, F., Jensen, P. B., Nielsen, S. J., & Sehested, M. (2010). Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase. B M C Cancer, 10(1), 677.