High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma

BACKGROUND: In spite of an initial good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinoma patients, resistance to treatment eventually occurs. Epidermal growth factor receptor (EGFR) activation stimulates Ras/Raf/Erk/MAPK and influences PI3K/Akt pathways, respectively. PHLPP negatively regulates PI3K/Akt and the RAF/RAS/ERK signaling pathways. Our study aimed to investigate the association between PH domain leucine-rich-repeats protein phosphatase (PHLPP) expression levels and the acquired resistance to EGFR TKIs in lung adenocarcinoma. RESULTS: High expression levels of PHLPP1 and PHLPP2 were detected in 69.3% and 61.3%, respectively, of patients with lung adenocarcinoma. Patients with high expression levels of PHLPP1 showed significantly longer median progression-free survival and overall survival than those with low expression levels of PHLPP1 (29 months versus 11 months, and 36 months versus 19 months respectively) (p = 0.0050 and p = 0.0052). PHLPP1, but not PHLPP2, protein expression levels was negatively correlated with p-Akt (473) and p-Erk1/2. The PHLPP1 expression levels were correlated with Progression-free survival and overall survival (p = 0.001 and p = 0.000). MATERIALS AND METHODS: We recruited 75 patients with advanced lung adenocarcinoma receiving EGFR TKIs treatment. The expression levels of PHLPP1, PHLPP2, p-AKT(S473) and p-ERK1/2 were assessed using tissue immunostaining. The association of PHLPP expression levels with clinicopathological parameters and disease prognosis was analyzed. CONCLUSIONS: This study suggests that high expression levels of PHLPP1 predict a better survival from target therapy and a longer time of acquired resistance to EGFR TKIs in patients with lung adenocarcinoma.