mPRα mediates P4/Org OD02‐0 to improve the sensitivity of lung adenocarcinoma to EGFR‐TKIs via the EGFR‐SRC‐ERK1/2 pathway

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.