mPRα mediates P4/Org OD02‐0 to improve the sensitivity of lung adenocarcinoma to EGFR‐TKIs via the EGFR‐SRC‐ERK1/2 pathway
| Autor: | Wei Li, Shaojin You, Shuya He, Qiong Chen, Baishuang Yang, Xi Chen, Anqi Guan, Xiaoxiao Lu, Mingxuan Xie, Jian Xiao |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Lung Neoplasms MAP Kinase Signaling System Mice Nude Adenocarcinoma 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Epidermal growth factor receptor Protein Kinase Inhibitors Molecular Biology Progesterone Mice Inbred BALB C biology Gefitinib Middle Aged medicine.disease Survival Analysis Xenograft Model Antitumor Assays In vitro Membrane progesterone receptor respiratory tract diseases ErbB Receptors Crosstalk (biology) src-Family Kinases 030104 developmental biology A549 Cells Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research biology.protein Female Receptors Progesterone Targeted therapy of lung cancer Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Molecular Carcinogenesis. 59:179-192 |
| ISSN: | 1098-2744 0899-1987 |
| Popis: | The discovery of epidermal growth factor receptor (EGFR) mutations has made EGFR tyrosine kinase inhibitors (EGFR-TKIs) a milestone in the treatment for advanced non-small cell lung cancer (NSCLC). However, patients lacking EGFR mutations are not sensitive to EGFR-TKI treatment and the emergence of secondary resistance poses new challenges for the targeted therapy of lung cancer. In this study, we identified that the expression of membrane progesterone receptor α (mPRα) was associated with EGFR mutations in lung adenocarcinoma patients and subsequently affected the efficacy of EGFR-TKIs. Progesterone (P4) or its derivative Org OD02-0 (Org), which is mediated by mPRα, increases the function of EGFR-TKIs to suppress the proliferation, migration, and invasion of lung adenocarcinoma cells in vitro and in vivo. In addition, the mPRα pathway triggers delayed resistance to EGFR-TKIs. Mechanistic investigations demonstrated that the mPRα pathway can crosstalk with the EGFR pathway by activating nongenomic effects to inhibit the EGFR-SRC-ERK1/2 pathway, thereby promoting antitumorigenic effects. In conclusion, our data describe an essential role for mPRα in improving sensitivity to EGFR-TKIs, thus rationalizing its potential as a therapeutic target for lung adenocarcinomas. |
| Databáze: | OpenAIRE |
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