TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data

Ann Katrine Jakobsen; Sakineh Yuusufi; Line Bille Madsen; Peter Meldgaard; Birgitta R. Knudsen; Magnus Stougaard

doi:10.1016/j.lungcan.2021.12.010

TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data

Ann Katrine Jakobsen, Sakineh Yuusufi, Line Bille Madsen, Peter Meldgaard, Birgitta R. Knudsen, Magnus Stougaard^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Objectives: Topoisomerase 1 (TOP1) is a drug target used in anticancer treatment of various cancer types. The effect of the TOP1 drugs can be counteracted by the enzymatic activity of tyrosyl-DNA phosphodiesterase 1 (TDP1). Thus, to elucidate the relevance of combining TDP1 and TOP1 as drug targets for anticancer treatment in NSCLC, TDP1 and TOP1 was for the first time quantified in a large cohort of paired normal and tumor tissue from NSCLC patients, and data were correlated between the two enzymes and to clinical data. Materials and methods: TDP1 and TOP1 activity and protein concentration were measured in paired normal and tumor tissue from 150 NSCLC patients using TDP1 and TOP1 specific biosensors and ELISA. TDP1 and TOP1 activity and protein concentration were correlated to clinical data. Results: TDP1 and TOP1 activity and protein concentration were significantly upregulated from normal to tumor tissue for the individual patients, but did not correlate to any of the clinical data. TDP1 and TOP1 activity were upregulated in 89.3% and 82.7% of the patients, respectively, and correlated in both normal and tumor tissue. The same tendency was observed for protein concentration with an upregulation of TDP1 and TOP1 in 73.0% and 84.4% of the patients, respectively. The activity and protein concentration correlated in normal and tumor tissue for both TDP1 and TOP1. Conclusion: The upregulations of TDP1 and TOP1 from normal to tumor tissue combined with the observation that TDP1 and TOP1 did not correlate to any of the clinical data indicate that both proteins are important for development or maintenance of the tumor cells in NSCLC. Correlations between TDP1 and TOP1 indicate a biological dependency and potential co-regulation of the enzymes. These observations is encouraging in relation to using TOP1 and TDP1 as targets in anticancer treatment of NSCLC.

Original language	English
Journal	Lung Cancer
Volume	164
Pages (from-to)	23-32
Number of pages	10
ISSN	0169-5002
DOIs	https://doi.org/10.1016/j.lungcan.2021.12.010 https://doi.org/10.1016/j.lungcan.2021.12.010
Publication status	Published - Feb 2022

Keywords

Biosensor
Non-small cell lung cancer
Precision medicine
Targeted therapy
Topoisomerase 1
Tyrosyl-DNA phosphodiesterase 1
Humans
Lung Neoplasms/drug therapy
Carcinoma, Non-Small-Cell Lung/drug therapy
DNA Topoisomerases, Type I
Phosphoric Diester Hydrolases/genetics

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1-s2.0-S0169500221006383-mainFinal published version, 3.04 MBLicence: CC BY

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Jakobsen, A. K., Yuusufi, S., Madsen, L. B., Meldgaard, P., Knudsen, B. R., & Stougaard, M. (2022). TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data. Lung Cancer, 164, 23-32. https://doi.org/10.1016/j.lungcan.2021.12.010, https://doi.org/10.1016/j.lungcan.2021.12.010

@article{05d8dc980db143c9ad57f8da63558d2f,

title = "TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data",

abstract = "Objectives: Topoisomerase 1 (TOP1) is a drug target used in anticancer treatment of various cancer types. The effect of the TOP1 drugs can be counteracted by the enzymatic activity of tyrosyl-DNA phosphodiesterase 1 (TDP1). Thus, to elucidate the relevance of combining TDP1 and TOP1 as drug targets for anticancer treatment in NSCLC, TDP1 and TOP1 was for the first time quantified in a large cohort of paired normal and tumor tissue from NSCLC patients, and data were correlated between the two enzymes and to clinical data. Materials and methods: TDP1 and TOP1 activity and protein concentration were measured in paired normal and tumor tissue from 150 NSCLC patients using TDP1 and TOP1 specific biosensors and ELISA. TDP1 and TOP1 activity and protein concentration were correlated to clinical data. Results: TDP1 and TOP1 activity and protein concentration were significantly upregulated from normal to tumor tissue for the individual patients, but did not correlate to any of the clinical data. TDP1 and TOP1 activity were upregulated in 89.3% and 82.7% of the patients, respectively, and correlated in both normal and tumor tissue. The same tendency was observed for protein concentration with an upregulation of TDP1 and TOP1 in 73.0% and 84.4% of the patients, respectively. The activity and protein concentration correlated in normal and tumor tissue for both TDP1 and TOP1. Conclusion: The upregulations of TDP1 and TOP1 from normal to tumor tissue combined with the observation that TDP1 and TOP1 did not correlate to any of the clinical data indicate that both proteins are important for development or maintenance of the tumor cells in NSCLC. Correlations between TDP1 and TOP1 indicate a biological dependency and potential co-regulation of the enzymes. These observations is encouraging in relation to using TOP1 and TDP1 as targets in anticancer treatment of NSCLC.",

keywords = "Biosensor, Non-small cell lung cancer, Precision medicine, Targeted therapy, Topoisomerase 1, Tyrosyl-DNA phosphodiesterase 1, Humans, Lung Neoplasms/drug therapy, Carcinoma, Non-Small-Cell Lung/drug therapy, DNA Topoisomerases, Type I, Phosphoric Diester Hydrolases/genetics",

author = "Jakobsen, {Ann Katrine} and Sakineh Yuusufi and Madsen, {Line Bille} and Peter Meldgaard and Knudsen, {Birgitta R.} and Magnus Stougaard",

year = "2022",

month = feb,

doi = "10.1016/j.lungcan.2021.12.010",

language = "English",

volume = "164",

pages = "23--32",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

Jakobsen, AK, Yuusufi, S, Madsen, LB , Meldgaard, P , Knudsen, BR & Stougaard, M 2022, 'TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data', Lung Cancer, vol. 164, pp. 23-32. https://doi.org/10.1016/j.lungcan.2021.12.010, https://doi.org/10.1016/j.lungcan.2021.12.010

TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data. / Jakobsen, Ann Katrine; Yuusufi, Sakineh; Madsen, Line Bille et al.
In: Lung Cancer, Vol. 164, 02.2022, p. 23-32.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - TDP1 and TOP1 as targets in anticancer treatment of NSCLC

T2 - Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data

AU - Jakobsen, Ann Katrine

AU - Yuusufi, Sakineh

AU - Madsen, Line Bille

AU - Meldgaard, Peter

AU - Knudsen, Birgitta R.

AU - Stougaard, Magnus

PY - 2022/2

Y1 - 2022/2

N2 - Objectives: Topoisomerase 1 (TOP1) is a drug target used in anticancer treatment of various cancer types. The effect of the TOP1 drugs can be counteracted by the enzymatic activity of tyrosyl-DNA phosphodiesterase 1 (TDP1). Thus, to elucidate the relevance of combining TDP1 and TOP1 as drug targets for anticancer treatment in NSCLC, TDP1 and TOP1 was for the first time quantified in a large cohort of paired normal and tumor tissue from NSCLC patients, and data were correlated between the two enzymes and to clinical data. Materials and methods: TDP1 and TOP1 activity and protein concentration were measured in paired normal and tumor tissue from 150 NSCLC patients using TDP1 and TOP1 specific biosensors and ELISA. TDP1 and TOP1 activity and protein concentration were correlated to clinical data. Results: TDP1 and TOP1 activity and protein concentration were significantly upregulated from normal to tumor tissue for the individual patients, but did not correlate to any of the clinical data. TDP1 and TOP1 activity were upregulated in 89.3% and 82.7% of the patients, respectively, and correlated in both normal and tumor tissue. The same tendency was observed for protein concentration with an upregulation of TDP1 and TOP1 in 73.0% and 84.4% of the patients, respectively. The activity and protein concentration correlated in normal and tumor tissue for both TDP1 and TOP1. Conclusion: The upregulations of TDP1 and TOP1 from normal to tumor tissue combined with the observation that TDP1 and TOP1 did not correlate to any of the clinical data indicate that both proteins are important for development or maintenance of the tumor cells in NSCLC. Correlations between TDP1 and TOP1 indicate a biological dependency and potential co-regulation of the enzymes. These observations is encouraging in relation to using TOP1 and TDP1 as targets in anticancer treatment of NSCLC.

AB - Objectives: Topoisomerase 1 (TOP1) is a drug target used in anticancer treatment of various cancer types. The effect of the TOP1 drugs can be counteracted by the enzymatic activity of tyrosyl-DNA phosphodiesterase 1 (TDP1). Thus, to elucidate the relevance of combining TDP1 and TOP1 as drug targets for anticancer treatment in NSCLC, TDP1 and TOP1 was for the first time quantified in a large cohort of paired normal and tumor tissue from NSCLC patients, and data were correlated between the two enzymes and to clinical data. Materials and methods: TDP1 and TOP1 activity and protein concentration were measured in paired normal and tumor tissue from 150 NSCLC patients using TDP1 and TOP1 specific biosensors and ELISA. TDP1 and TOP1 activity and protein concentration were correlated to clinical data. Results: TDP1 and TOP1 activity and protein concentration were significantly upregulated from normal to tumor tissue for the individual patients, but did not correlate to any of the clinical data. TDP1 and TOP1 activity were upregulated in 89.3% and 82.7% of the patients, respectively, and correlated in both normal and tumor tissue. The same tendency was observed for protein concentration with an upregulation of TDP1 and TOP1 in 73.0% and 84.4% of the patients, respectively. The activity and protein concentration correlated in normal and tumor tissue for both TDP1 and TOP1. Conclusion: The upregulations of TDP1 and TOP1 from normal to tumor tissue combined with the observation that TDP1 and TOP1 did not correlate to any of the clinical data indicate that both proteins are important for development or maintenance of the tumor cells in NSCLC. Correlations between TDP1 and TOP1 indicate a biological dependency and potential co-regulation of the enzymes. These observations is encouraging in relation to using TOP1 and TDP1 as targets in anticancer treatment of NSCLC.

KW - Biosensor

KW - Non-small cell lung cancer

KW - Precision medicine

KW - Targeted therapy

KW - Topoisomerase 1

KW - Tyrosyl-DNA phosphodiesterase 1

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - DNA Topoisomerases, Type I

KW - Phosphoric Diester Hydrolases/genetics

UR - http://www.scopus.com/inward/record.url?scp=85121907584&partnerID=8YFLogxK

U2 - 10.1016/j.lungcan.2021.12.010

DO - 10.1016/j.lungcan.2021.12.010

M3 - Journal article

C2 - 34974222

AN - SCOPUS:85121907584

SN - 0169-5002

VL - 164

SP - 23

EP - 32

JO - Lung Cancer

JF - Lung Cancer

ER -

TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data

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