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.
Mol Carcinog. 2020 Feb;59(2):179-192. doi: 10.1002/mc.23139. Epub 2019 Nov 28.
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.
表皮生长因子受体 (EGFR) 突变的发现使 EGFR 酪氨酸激酶抑制剂 (EGFR-TKIs) 成为治疗晚期非小细胞肺癌 (NSCLC) 的里程碑。然而，缺乏 EGFR 突变的患者对 EGFR-TKI 治疗不敏感，而继发性耐药的出现为肺癌的靶向治疗带来了新的挑战。在本研究中，我们发现膜孕激素受体 α (mPRα) 的表达与肺腺癌患者的 EGFR 突变相关，并随后影响 EGFR-TKIs 的疗效。孕激素 (P4) 或其衍生物 Org OD02-0 (Org) 通过 mPRα 介导，增加 EGFR-TKIs 的功能，抑制肺腺癌细胞在体外和体内的增殖、迁移和侵袭。此外，mPRα 通路引发了对 EGFR-TKIs 的延迟耐药。机制研究表明，mPRα 通路可以通过激活非基因组效应与 EGFR 通路相互作用，抑制 EGFR-SRC-ERK1/2 通路，从而促进抗肿瘤作用。总之，我们的数据描述了 mPRα 在提高 EGFR-TKIs 敏感性方面的重要作用，从而合理地将其作为肺腺癌的治疗靶点。
