Dna polymerase alpha subunit b is a binding protein for erlotinib resistance in non-small cell lung cancer

Tae Young Kim; Eun Sun Ji; Ju Yeon Lee; Jin Young Kim; Jong Shin Yoo; A. Marcell Szasz; Balazs Dome; Gyorgy Marko-Varga; Ho Jeong Kwon

doi:10.3390/cancers12092613

Dna polymerase alpha subunit b is a binding protein for erlotinib resistance in non-small cell lung cancer

Tae Young Kim, Eun Sun Ji, Ju Yeon Lee, Jin Young Kim, Jong Shin Yoo, A. Marcell Szasz, Balazs Dome, Gyorgy Marko-Varga, Ho Jeong Kwon

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas the overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy (Pearson correlation coefficient, R = 0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.

Original language	English
Article number	2613
Pages (from-to)	1-14
Number of pages	14
Journal	Cancers
Volume	12
Issue number	9
DOIs	https://doi.org/10.3390/cancers12092613
Publication status	Published - 2020 Sept

Bibliographical note

Funding Information:
Funding: This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900), Brain Korea 21 Plus Project, the Korea Basic Science Institute (KBSI; Research Grant No. C060100) and ICONS (Institute of Convergence Science), Yonsei University, Republic of Korea as well as the Berta Kamprad Foundation, Lund, Sweden.

Funding Information:
This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900), Brain Korea 21 Plus Project, the Korea Basic Science Institute (KBSI; Research Grant No. C060100) and ICONS (Institute of Convergence Science), Yonsei University, Republic of Korea as well as the Berta Kamprad Foundation, Lund, Sweden. Acknowledgments: The authors are grateful to Ho-young Lee (Seoul National University, Seoul, Korea) for providing NSCLC cell lines (HCC827, PC9, H1299, and A549).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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title = "Dna polymerase alpha subunit b is a binding protein for erlotinib resistance in non-small cell lung cancer",

abstract = "Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas the overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy (Pearson correlation coefficient, R = 0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.",

author = "Kim, {Tae Young} and Ji, {Eun Sun} and Lee, {Ju Yeon} and Kim, {Jin Young} and Yoo, {Jong Shin} and {Marcell Szasz}, A. and Balazs Dome and Gyorgy Marko-Varga and Kwon, {Ho Jeong}",

note = "Funding Information: Funding: This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900), Brain Korea 21 Plus Project, the Korea Basic Science Institute (KBSI; Research Grant No. C060100) and ICONS (Institute of Convergence Science), Yonsei University, Republic of Korea as well as the Berta Kamprad Foundation, Lund, Sweden. Funding Information: This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900), Brain Korea 21 Plus Project, the Korea Basic Science Institute (KBSI; Research Grant No. C060100) and ICONS (Institute of Convergence Science), Yonsei University, Republic of Korea as well as the Berta Kamprad Foundation, Lund, Sweden. Acknowledgments: The authors are grateful to Ho-young Lee (Seoul National University, Seoul, Korea) for providing NSCLC cell lines (HCC827, PC9, H1299, and A549). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = sep,

doi = "10.3390/cancers12092613",

language = "English",

volume = "12",

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T1 - Dna polymerase alpha subunit b is a binding protein for erlotinib resistance in non-small cell lung cancer

AU - Kim, Tae Young

AU - Ji, Eun Sun

AU - Lee, Ju Yeon

AU - Kim, Jin Young

AU - Yoo, Jong Shin

AU - Marcell Szasz, A.

AU - Dome, Balazs

AU - Marko-Varga, Gyorgy

AU - Kwon, Ho Jeong

N1 - Funding Information: Funding: This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900), Brain Korea 21 Plus Project, the Korea Basic Science Institute (KBSI; Research Grant No. C060100) and ICONS (Institute of Convergence Science), Yonsei University, Republic of Korea as well as the Berta Kamprad Foundation, Lund, Sweden. Funding Information: This work was partly supported by grants from the National Research Foundation of Korea and was funded by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900), Brain Korea 21 Plus Project, the Korea Basic Science Institute (KBSI; Research Grant No. C060100) and ICONS (Institute of Convergence Science), Yonsei University, Republic of Korea as well as the Berta Kamprad Foundation, Lund, Sweden. Acknowledgments: The authors are grateful to Ho-young Lee (Seoul National University, Seoul, Korea) for providing NSCLC cell lines (HCC827, PC9, H1299, and A549). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/9

Y1 - 2020/9

N2 - Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas the overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy (Pearson correlation coefficient, R = 0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.

AB - Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas the overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy (Pearson correlation coefficient, R = 0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.

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ER -

Dna polymerase alpha subunit b is a binding protein for erlotinib resistance in non-small cell lung cancer

Abstract

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