Comparison of EMT mediated tyrosine kinase inhibitor resistance in NSCLC

Abstract

In the United States, lung cancer is the second most common cancer in men and women. In 2017, 222,500 new cases and 155,870 deaths from lung cancer are estimated to have occurred. A tyrosine kinase receptor, epidermal growth factor receptor (EGFR), is over expressed or mutated in non-small cell lung cancer (NSCLC) resulting in increased cell proliferation and survival. Tyrosine kinase inhibitors (TKIs) are currently being used as therapy for NSCLC patients, however, they have limited efficacy in NSCLC patients due to acquisition of resistance. This study investigates the role of epithelial-mesenchymal transition (EMT) in the development of resistance against TKIs in NSCLC. Currently, the role of p120-catenin, Kaiso factor and PRMT-1 in reversal of EMT in T790M mutated and TKI-resistant NSCLC cells is a new line of study. In this investigation we found upregulation of cytoplasmic p120-catenin, which was co-localized with Kaiso factor. In the nucleus, binding of p120-catenin to Kaiso factor initiates transcription by activating EMT-transcription factors such as Snail, Slug, Twist, and ZEB1. PRMT-1 was also found to be upregulated, which induces methylation of Twist and repression of E-cadherin activity, thus promoting EMT. We confirmed that TKI-resistant cells have mesenchymal cell type characteristics based on their cell morphology and gene or protein expression of EMT related proteins. EMT proteins, Vimentin and N-cadherin, displayed increased expression, whereas E-cadherin expression was downregulated. Finally, we found that the knockdown of p120-catenin and PRMT-1 by siRNA or use of a PRMT-1 inhibitor Furamidine increased Erlotinib sensitivity and could reverse EMT to overcome TKI resistance.

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

“…Interestingly, TKI-resistant NSCLC cells also exhibited low levels of E-cadherin expression and high expression of EMT markers such as Twist, Slug and Snail. This is in contrast to TKI-sensitive NSCLC cells, where E-cadherin was expressed and low levels of the aforementioned EMT markers were observed [69]. Given the dependence of the Kaiso-p120 ctn interaction on the status of p120 ctn phosphorylation [68], it is possible that p120 ctn is hyper-phosphorylated in TKI-resistant NSCLC cells, resulting in its sequestration by Kaiso and consequently, a reduction in E-cadherin protein stability concomitant with increased cell motility or metastasis.…”

“…They further showed that higher levels of Kaiso co-precipitated with phosphorylated p120 ctn compared to unphosphorylated p120 ctn , suggesting that serine-288 phosphorylation may act as the molecular switch that mediates p120 ctn -Kaiso binding in lung cancer cells [68]. Most recently, Iderzorig et al [69] found that p120 ctn co-localizes with Kaiso in the nucleus in tyrosine kinase inhibitor (TKI)-resistant NSCLC cells, while in TKI-sensitive NSCLC cells reduced co-localization was observed. Interestingly, TKI-resistant NSCLC cells also exhibited low levels of E-cadherin expression and high expression of EMT markers such as Twist, Slug and Snail.…”

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

“…The gatekeeper mutants of EGFR, PDGFR, c-ABL, and Src were shown to have activated kinase activity and an increased rate of cellular transformation (16). In addition, the EGFR T790M gatekeeper mutation has been shown to promote EMT (28)(29)(30). Previous studies in our lab have kinetically characterized V561M FGFR1 and demonstrated an increase in the k cat of V561M FGFR1 relative to wild type (WT).…”

Lung Cancer Therapy Targeting Histone Methylation: Opportunities and Challenges

“…For instance, silencing PRMT1 decreased a mitogenic factor called Neuromedin B receptor while increased epithelial markers cytokeratins 7 and 8, which consequently resulted in reduced cell proliferation and enhanced tumor differentiation [ 134 ]. Additionally, up-regulated PRMT1 repressed E-cadherin activity and promoted EMT in erlotinib-resistant NSCLC cells (erlotinib is a tyrosine kinase inhibitor against NSCLC) [ 135 ].…”