The Role of Non-Coding RNA Editing in MET Signaling in NSCLC

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PROJECT SUMMARY Lung cancer is the primary cause of cancer-related deaths in the U.S. Despite encouraging progress in creating new therapeutics, most lung cancer patients develop resistance and succumb to metastatic disease. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is frequently mutated in lung cancer (10-50%). Several EGFR inhibitors have been developed to mitigate the transformative effects of mutant EGFR. For example, gefitinib and osimertinib are tyrosine kinase inhibitors (TKIs) used for treating EGFR- mutated non-small cell lung cancer (NSCLC). Unfortunately, despite the initial responsiveness of patients to these drugs, a rapidly acquired resistance occurs mainly because of new genetic alterations, including amplification of the hepatocyte growth factor receptor (MET). Adenosine to Inosine (A-to-I) RNA editing represents 90% of all the RNA editing events in the cell and regulates mRNA sequence, function, degradation, and structure. RNA editing has been observed in both coding and non- coding genes, including miRs. Furthermore, coding RNA editing dysregulation has been recently associated with cancerous phenotype and drug resistance, including against TKIs. Recent high throughput interrogation of the human genome has allowed for the identification of miR editing deregulation in cancer. However, the biological impact of edited non-coding RNAs (i.e., miRs) in lung cancer progression and drug resistance remains largely unknown. We preliminarily identified a reduction of A-to-I editing in position 5 of miR-411-5p in the tissues of lung cancer patients. We determined that ed.miR-411-5p negatively affects the ERK1/2 pathway, directly targets MET, and alters TKI drug resistance in NSCLC cell lines. Furthermore, it is reported that MET transcriptionally regulates the expression of miR-222. We have also found that the miR-222 targets ADAR2, a member of the ADAR proteins family, responsible for pre-mRNA and non-coding RNA A-to-I editing. ADAR2 also induces A-to-I editing in miRs, including miR-411-5p. We found that ADAR2 is downregulated in lung cancer tissues and TKI resistant tissue and cell lines and anticorrelates with miR-222 expression. We hypothesize that miR editing dysregulation contributes to the pathobiology of lung cancer. Therefore, we aim to globally evaluate the impact that ed.miR-411-5p has on NSCLC progression and TKI resistance. Then, we also intend to investigate by RNA seq. if the ed.miR-411-5p induces ADAR2 expression and activity through MET, ERK1/2, and miR-222 signaling repression with the scope of uncovering new post-transcriptional mechanisms that regulate lung cancer progression and drug resistance.