Abstract 485: Modulation of microRNA expression in EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cell lines

Abstract

Abstract Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now standard of care in lung cancer patients with EGFR mutation. Invariably, these patients develop resistance and require treatment with another EGFR-TKI or chemotherapy. The gatekeeper mutation T790M is responsible for about 50% of resistance. Other mechanisms may also confer resistance in these patients. High expression of microRNA-10b (miRNA-10b) is associated with worse prognosis in resected lung cancer patients with EGFR mutation. Both miRNA-27a and -27b are associated with increased expression of c-met, which is a potential mechanism of resistance to EGFR-TKI. The goal of this study is to determine the optimal treatment and miRNA characteristic of EGFR mutation lung cancer cells resistant to EGFR-TKI. We hypothesized that miRNA-10b, -27a and -27b modulated Erlotinib (ERL) resistance by different EGFR-TKIs and chemotherapeutic agents in EGFR mutant NSCLC cell lines. Materials and Methods: Lung cancer cell lines with EGFR mutation HCC827 and HCC4006 resistant to ERL were generated. ERL-resistant cells were then treated with 10 nM afatinib (Afa), 0.5 mg/mL pemetrexed (Pem), and combination of 10 nM Afa/0.5mg/mL Pem for 72h. The cells were harvested and microRNA assay was performed by real-time PCR. NCI-H460 cell line without EGFR mutation was used as control. Results: We observed increased expression of miRNA-10b, miRNA-27a and miRNA-27b in ERL-resistant HCC4006 compared to control cells NCI-H460. There was an upregulation of miRNA-27a and -27b but not of miRNA-10b in ERL-resistant HCC827. Treatment of ERL-resistant cells with Afa, Pem, and combined treatment changed the expression of miRNA-10b, miRNA-27a and miRNA-27b. These miRNAs were downregulated by 2nd-generation EGFR-TKI therapy alone or in combination with Pem. Different treatments had different effects on these miRNAs. There might be differences in miRNA regulation in different cell lines when treated with EGFR-TKI or chemotherapy. Our results suggest that microRNA may be used as targets for developing novel approach to treating patients with EGFR-TKI resistance. Conclusion: This study may have implications in the management of patients resistant to EGFR TKI. MicroRNA analysis showed upregulation of several microRNAs that should be confirmed in clinical setting. Citation Format: Inamul Haque, Hannah Motes, Mukut Sharma, Emma Borrego-Diaz Reyes, Andrew K. Godwin, Chao H. Huang. Modulation of microRNA expression in EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 485.