mPRalpha mediates P4/Org OD02-0 to improve the sensitivity of lung adenocarcinoma to EGFR-TKIs via the EGFR-SRC-ERK1/2 pathway
mPRalpha mediates P4/Org OD02-0 to improve the sensitivity of lung adenocarcinoma to EGFR-TKIs via the EGFR-SRC-ERK1/2 pathway
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mPRalpha介导P4/Org OD02-0通过EGFR-SRC-ERK1/2通路提高肺腺癌对EGFR-TKIs的敏感性
DOI：
10.1002/mc.23139
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发表时间：
2020
影响因子：
4.6
通讯作者：
Chen Qiong
中科院分区：
文献类型：
--
作者：
Lu Xiaoxiao;Guan Anqi;Chen Xi;Xiao Jian;Xie Mingxuan;Yang Baishuang;He Shuya;You Shaojin;Li Wei;Chen Qiong
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-TKI）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，继发性耐药的出现为肺癌靶向治疗带来了新的挑战。在本研究中，我们确定了肺腺癌患者中膜孕酮受体α（mPRα）的表达与EGFR突变相关，并随后影响EGFR-TKI的疗效。由mPRα介导的Progressive（P4）或其衍生物Progressive OD 02 - 0（Progressive OD 02 - 0，Progres此外，mPRα通路触发对EGFR‐ TKI的延迟耐药。机制研究表明，mPRα通路可通过激活非基因组效应与EGFR通路发生串扰，从而抑制EGFR-SRC-ERK 1/2通路，从而促进抗肿瘤作用。总之，我们的数据描述了mPRα在改善EGFR‐ TKI敏感性方面的重要作用，从而证明了其作为肺腺癌治疗靶点的潜力。
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.