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

Uffe Høgh Olesen; Jakob Gramstrup Petersen; Antje Garten; Wieland Kiess; Jun Yoshino; Shin-Ichiro Imai; Mette Knak Christensen; Peter Fristrup; Annemette Vinding Thougaard; Fredrik Björkling; Peter Buhl Jensen; Søren Jensby Nielsen; Maxwell Sehested

doi:10.1186/1471-2407-10-677

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

Uffe Høgh Olesen, Jakob Gramstrup Petersen, Antje Garten, Wieland Kiess, Jun Yoshino, Shin-Ichiro Imai, Mette Knak Christensen, Peter Fristrup, Annemette Vinding Thougaard, Fredrik Björkling, Peter Buhl Jensen, Søren Jensby Nielsen, Maxwell Sehested

37 Citations (Scopus)

Abstract

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 language	English
Journal	BMC Cancer
Volume	10
Pages (from-to)	677
Number of pages	13
ISSN	1471-2407
DOIs	https://doi.org/10.1186/1471-2407-10-677
Publication status	Published - 12 Dec 2010

Keywords

Faculty of Health and Medical Sciences

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/1471-2407-10-677

http://www.biomedcentral.com/1471-2407/10/677

Cite this

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. BMC Cancer, 10, 677. https://doi.org/10.1186/1471-2407-10-677

Olesen, UH, Petersen, JG, Garten, A, Kiess, W, Yoshino, J, Imai, S-I, Christensen, MK, Fristrup, P, Thougaard, AV, Björkling, F, Jensen, PB, Nielsen, SJ & Sehested, M 2010, 'Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase', BMC Cancer, vol. 10, pp. 677. https://doi.org/10.1186/1471-2407-10-677

@article{508a791fb1a24346bfbedea6a2f83a9a,

title = "Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase",

abstract = "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.",

keywords = "Faculty of Health and Medical Sciences",

author = "Olesen, {Uffe H{\o}gh} and Petersen, {Jakob Gramstrup} and Antje Garten and Wieland Kiess and Jun Yoshino and Shin-Ichiro Imai and Christensen, {Mette Knak} and Peter Fristrup and Thougaard, {Annemette Vinding} and Fredrik Bj{\"o}rkling and Jensen, {Peter Buhl} and Nielsen, {S{\o}ren Jensby} and Maxwell Sehested",

year = "2010",

month = dec,

day = "12",

doi = "10.1186/1471-2407-10-677",

language = "English",

volume = "10",

pages = "677",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase

AU - Olesen, Uffe Høgh

AU - Petersen, Jakob Gramstrup

AU - Garten, Antje

AU - Kiess, Wieland

AU - Yoshino, Jun

AU - Imai, Shin-Ichiro

AU - Christensen, Mette Knak

AU - Fristrup, Peter

AU - Thougaard, Annemette Vinding

AU - Björkling, Fredrik

AU - Jensen, Peter Buhl

AU - Nielsen, Søren Jensby

AU - Sehested, Maxwell

PY - 2010/12/12

Y1 - 2010/12/12

N2 - 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.

AB - 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.

KW - Faculty of Health and Medical Sciences

U2 - 10.1186/1471-2407-10-677

DO - 10.1186/1471-2407-10-677

M3 - Journal article

C2 - 21144000

SN - 1471-2407

VL - 10

SP - 677

JO - BMC Cancer

JF - BMC Cancer

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this