| Institution: | 1. Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;2. Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China;3. Department of Respiratory, Xiangya Hospital, Central South University, Changsha, Hunan, China;4. Department of Biochemistry & Biology, University of South China, Hengyang, China;5. Laboratory of Cancer Experimental Therapy, Histopathology Core, Atlanta Research & Educational Foundation (151F), Atlanta VA Medical Center, Emory University, Decatur, Georgia;6. Department of Geriatrics, Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China |
| Abstract: | 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. |
