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

Kim, Tae Young ; Ji, Eun Sun ; Lee, Ju Yeon ; Kim, Jin Young ; Yoo, Jong Shin ; Marcell Szasz, A. LU ; Dome, Balazs ; Marko-Varga, Gyorgy LU and Kwon, Ho Jeong LU (2020) In Cancers 12(9). p.1-14
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.... (More)

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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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DARTS LC-MS/MS, Erlotinib, NSCLC, POLA2, Resistance
in
Cancers
volume
12
issue
9
article number
2613
pages
14 pages
publisher
Multidisciplinary Digital Publishing Institute (MDPI)
external identifiers
  • scopus:85090756679
  • pmid:32933200
ISSN
2072-6694
DOI
10.3390/cancers12092613
language
English
LU publication?
yes
id
dd4e49b5-5f27-431a-819b-bc26aa566839
date added to LUP
2020-10-01 13:43:29
date last changed
2021-06-08 01:24:59
@article{dd4e49b5-5f27-431a-819b-bc26aa566839,
  abstract     = {<p>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.</p>},
  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 Dome, Balazs and Marko-Varga, Gyorgy and Kwon, Ho Jeong},
  issn         = {2072-6694},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {1--14},
  publisher    = {Multidisciplinary Digital Publishing Institute (MDPI)},
  series       = {Cancers},
  title        = {Dna polymerase alpha subunit b is a binding protein for erlotinib resistance in non-small cell lung cancer},
  url          = {http://dx.doi.org/10.3390/cancers12092613},
  doi          = {10.3390/cancers12092613},
  volume       = {12},
  year         = {2020},
}