PRMT-1 and p120-Catenin as EMT Mediators in Osimertinib Resistance in NSCLC
Author:
Racherla Kavya Sri1, Dovalovsky Katrina1, Patel Meet1ORCID, Harper Emma1, Barnard Jacob1, Nasifuzzaman S M1, Smith Mason1, Sikand Riya1, Drinka Eva2, Puri Neelu1
Affiliation:
1. Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA 2. Department of Pathology, University of Wisconsin Health, Swedish American Hospital, Rockford, IL 61104, USA
Abstract
Osimertinib, an irreversible tyrosine kinase inhibitor, is a first-line therapy in EGFR-mutant NSCLC patients. Prolonged treatment with Osimertinib leads to resistance due to an acquired C797S mutation in the EGFR domain and other mechanisms, such as epithelial-mesenchymal transition (EMT). In this study, we investigated the role of PRMT-1 and p120-catenin in mediating Osimertinib resistance (OR) through EMT. These studies found upregulation of gene and protein expression of PRMT-1, p120-catenin and Kaiso factor. Knockdown of p120-catenin using siRNA increased OR efficacy by 45% as compared to cells treated with mock siRNA and OR. After 24 h of transfection, the percentage wound closure in cells transfected with p120-catenin siRNA was 26.2%. However, in mock siRNA-treated cells the wound closure was 7.4%, showing its involvement in EMT. We also found high levels of p120-catenin expressed in 30% of smokers as compared to 5.5% and 0% of non-smokers and quit-smokers (respectively) suggesting that smoking may influence p120-catenin expression in NSCLC patients. These results suggest that biomarkers such as PRMT-1 may mediate EMT by methylating Twist-1 and increasing p120-catenin expression, which causes transcriptional activation of genes associated with Kaiso factor to promote EMT in Osimertinib-resistant cells.
Subject
Cancer Research,Oncology
Reference41 articles.
1. Cancer statistics, 2023;Siegel;CA A Cancer J. Clin.,2023 2. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship;Molina;Mayo Clin. Proc.,2008 3. Using whole genome amplification (WGA) of low-volume biopsies to assess the prognostic role of EGFR, KRAS, p53, and CMET mutations in advanced-stage non-small cell lung cancer (NSCLC);Lim;J. Thorac. Oncol.,2009 4. 5-year overall survival in patients with lung cancer eligible or ineligible for screening according to US Preventive Services Task Force criteria: A prospective, observational cohort study;Luo;Lancet Oncol.,2019 5. Schrank, Z., Chhabra, G., Lin, L., Iderzorig, T., Osude, C., Khan, N., Kuckovic, A., Singh, S., Miller, R.J., and Puri, N. (2018). Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance. Cancers, 10.
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