The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors

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

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: EGFR inhibitors; oral squamous cell carcinoma (OSCC); polymorphism; periplakin
Subjects: R Medicine
R Medicine > RK Dentistry
Divisions: Faculty of Dentistry > Dept of General Dental Practice And Oral & Maxillofacial Imaging
Depositing User: Mr Ahmad Azwan Azman
Date Deposited: 21 Feb 2020 03:32
Last Modified: 21 Feb 2020 03:32
URI: http://eprints.um.edu.my/id/eprint/23887

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