The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors
The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by compa...
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2019
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my.um.eprints.238872020-02-21T03:32:54Z http://eprints.um.edu.my/23887/ The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors Lee, Hui Mei Kelly, Gregory Michael Zainal, Nur Syafinaz Yee, Pei San Fadlullah, Muhammad Zaki Hidayatullah Lee, Bernard Kok Bang Gan, Chai Phei Patel, Vyomesh Cheong, Sok Ching R Medicine RK Dentistry The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted. Nature Research 2019 Article PeerReviewed text en http://eprints.um.edu.my/23887/1/s41598-019-38742-0.pdf Lee, Hui Mei and Kelly, Gregory Michael and Zainal, Nur Syafinaz and Yee, Pei San and Fadlullah, Muhammad Zaki Hidayatullah and Lee, Bernard Kok Bang and Gan, Chai Phei and Patel, Vyomesh and Cheong, Sok Ching (2019) The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors. Scientific Reports, 9. p. 2357. ISSN 2045-2322 https://www.nature.com/articles/s41598-019-38742-0.pdf doi:10.1186/s12903-019-0833-2 |
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R Medicine RK Dentistry Lee, Hui Mei Kelly, Gregory Michael Zainal, Nur Syafinaz Yee, Pei San Fadlullah, Muhammad Zaki Hidayatullah Lee, Bernard Kok Bang Gan, Chai Phei Patel, Vyomesh Cheong, Sok Ching The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors |
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The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted. |
format |
Article |
author |
Lee, Hui Mei Kelly, Gregory Michael Zainal, Nur Syafinaz Yee, Pei San Fadlullah, Muhammad Zaki Hidayatullah Lee, Bernard Kok Bang Gan, Chai Phei Patel, Vyomesh Cheong, Sok Ching |
author_facet |
Lee, Hui Mei Kelly, Gregory Michael Zainal, Nur Syafinaz Yee, Pei San Fadlullah, Muhammad Zaki Hidayatullah Lee, Bernard Kok Bang Gan, Chai Phei Patel, Vyomesh Cheong, Sok Ching |
author_sort |
Lee, Hui Mei |
title |
The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors |
title_short |
The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors |
title_full |
The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors |
title_fullStr |
The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors |
title_full_unstemmed |
The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors |
title_sort |
4717c > g polymorphism in periplakin modulates sensitivity to egfr inhibitors |
publisher |
Nature Research |
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2019 |
url |
http://eprints.um.edu.my/23887/1/s41598-019-38742-0.pdf http://eprints.um.edu.my/23887/ https://www.nature.com/articles/s41598-019-38742-0.pdf |
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1662755193123504128 |
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13.160551 |