5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer

Francesca Toffalorio, Mariacarmela Santarpia, Davide Radice, Christopher Adrian Jaramillo, Gianluca Spitaleri, Michela Manzotti, Chiara Catania, Lars Petter Jordheim, Giuseppe Pelosi, Godefridus J. Peters, Carmelo Tibaldi, Niccola Funel, Lorenzo Spaggiari, Filippo de Braud, Tommaso de Pas, Elisa Giovannetti

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/ progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.
LanguageEnglish
Pages16437-16450
JournalOncotarget
Volume9
Issue number23
DOIs
StatePublished - 2018

Cite this

Toffalorio, Francesca ; Santarpia, Mariacarmela ; Radice, Davide ; Jaramillo, Christopher Adrian ; Spitaleri, Gianluca ; Manzotti, Michela ; Catania, Chiara ; Jordheim, Lars Petter ; Pelosi, Giuseppe ; Peters, Godefridus J. ; Tibaldi, Carmelo ; Funel, Niccola ; Spaggiari, Lorenzo ; de Braud, Filippo ; de Pas, Tommaso ; Giovannetti, Elisa. / 5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer. In: Oncotarget. 2018 ; Vol. 9, No. 23. pp. 16437-16450
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title = "5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer",
abstract = "A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/ progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.",
author = "Francesca Toffalorio and Mariacarmela Santarpia and Davide Radice and Jaramillo, {Christopher Adrian} and Gianluca Spitaleri and Michela Manzotti and Chiara Catania and Jordheim, {Lars Petter} and Giuseppe Pelosi and Peters, {Godefridus J.} and Carmelo Tibaldi and Niccola Funel and Lorenzo Spaggiari and {de Braud}, Filippo and {de Pas}, Tommaso and Elisa Giovannetti",
year = "2018",
doi = "10.18632/oncotarget.24505",
language = "English",
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Toffalorio, F, Santarpia, M, Radice, D, Jaramillo, CA, Spitaleri, G, Manzotti, M, Catania, C, Jordheim, LP, Pelosi, G, Peters, GJ, Tibaldi, C, Funel, N, Spaggiari, L, de Braud, F, de Pas, T & Giovannetti, E 2018, '5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer' Oncotarget, vol. 9, no. 23, pp. 16437-16450. DOI: 10.18632/oncotarget.24505

5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer. / Toffalorio, Francesca; Santarpia, Mariacarmela; Radice, Davide; Jaramillo, Christopher Adrian; Spitaleri, Gianluca; Manzotti, Michela; Catania, Chiara; Jordheim, Lars Petter; Pelosi, Giuseppe; Peters, Godefridus J.; Tibaldi, Carmelo; Funel, Niccola; Spaggiari, Lorenzo; de Braud, Filippo; de Pas, Tommaso; Giovannetti, Elisa.

In: Oncotarget, Vol. 9, No. 23, 2018, p. 16437-16450.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - 5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer

AU - Toffalorio,Francesca

AU - Santarpia,Mariacarmela

AU - Radice,Davide

AU - Jaramillo,Christopher Adrian

AU - Spitaleri,Gianluca

AU - Manzotti,Michela

AU - Catania,Chiara

AU - Jordheim,Lars Petter

AU - Pelosi,Giuseppe

AU - Peters,Godefridus J.

AU - Tibaldi,Carmelo

AU - Funel,Niccola

AU - Spaggiari,Lorenzo

AU - de Braud,Filippo

AU - de Pas,Tommaso

AU - Giovannetti,Elisa

PY - 2018

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N2 - A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/ progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

AB - A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher's test. 5'-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/ progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

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Toffalorio F, Santarpia M, Radice D, Jaramillo CA, Spitaleri G, Manzotti M et al. 5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer. Oncotarget. 2018;9(23):16437-16450. Available from, DOI: 10.18632/oncotarget.24505