IGF-1R, E-cadherin, N-cadherin, and occludin gene expression and resistance to EGFR tyrosine-kinase inhibitors in patients with lung adenocarcinoma in Serbia.

person Vera Jokic Montefiore New Rochelle, New Rochelle, NY info_outline Vera Jokic, Milena Cavic, Jelena Spasic, Mladen Marinkovic, Katarina Savic Vujovic, Radmila Jankovic, Bojan Zaric

Authors person Vera Jokic Montefiore New Rochelle, New Rochelle, NY info_outline Vera Jokic, Milena Cavic, Jelena Spasic, Mladen Marinkovic, Katarina Savic Vujovic, Radmila Jankovic, Bojan Zaric Organizations Montefiore New Rochelle, New Rochelle, NY, Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia, Department of Medical Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia, Institute for oncology and radiology of Serbia, Belgrade, Serbia, University of Belgrade, Department of Pharmacology and Toxicology, Belgrade, Serbia, Institute for Oncology and Radiology, Beograd, Serbia, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Vojvodina, Serbia Abstract Disclosures Research Funding Ministry of Science, Technological Development and Innovation of the Republic of Serbia Science Fund of the Republic of Serbia, research Executive Agency, European Commission Background: Mutations in epidermal growth factor-receptor ( EGFR ) are found in approximately 10% of patients with lung adenocarcinoma in Serbia. EGFR tyrosine-kinase inhibitors ( EGFR -TKIs) is a safe and effective targeted therapy. However, most patients develop resistance. Acquired resistance to EGFR- TKI is defined as disease progression after achieving response or stable disease and there is a possible molecular association with epithelial-mesenchymal transition (EMT), particularly N-cadherin, E-cadherin, occludin and insulin-like growth factor-1 receptor (IGF-1R). We assessed the gene expression levels of IGF-1R, E-cadherin, N-cadherin, and occludin as predictive factors of resistance to EGFR -TKIs and survival outcomes in patients with advanced EGFR mutation-positive lung adenocarcinoma in Serbia. Methods: 101 patients with stage IIIB/IV EGFR mutation positive lung adenocarcinoma treated with EGFR -TKIs were included in the study. Quantitative RT-PCR was performed to determine mutations in EGFR , and expression of N-cadherin, E-cadherin, occludin and IGF-1R. Kaplan-Meier method was employed to estimate overall-survival (OS) and progression-free survival (PFS), with significance set at p<0.05. Results: Median age of patients was 61.7 (39 - 81) years, 65.3% were females and 91% were diagnosed with metastatic lung adenocarcinoma. EGFR mutations were more frequently detected in females (p <0.001). Median overall survival (OS) was 21 months (15.2–26.7 CI 95%) and progression-free survival (PFS) was 10 months (7.4-12.5 CI 95%). Patients whose tumors had lower levels of IGF-1R , and N-cadherin expression had statistically significantly longer PFS (p <0.001). Patients with lower levels of IGF-1R and higher levels of E-cadherin gene expression were more likely to have a complete or partial response to therapy (p = 0.04). There was a statistically significant association between elevated IGF-1R expression and the occurrence of EGFR- TKI resistance in patients (p <0.001). There was a statistically significant association between increased N-cadherin expression and reduced E-cadherin expression with EGFR- TKI resistance in patients. Conclusions: The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin. In this group of patients, higher levels of IGF-1R and N-cadherin gene expression were associated with shorter PFS and resistance to EGFR TKI, compared to higher levels of expression of E-cadherin, which may indicate potential value of expression of these genes in predicting acquired resistance to EGFR -TKI. Therefore, more research is needed to prove the potential predictive value of E-cadherin, N-cadherin and IFG-1R in acquired resistance to EGFR-TKI and developing novel therapeutic options with anti-EMT properties that can overcome this problem.