Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations

作者：Wang, Zhijie; Shen, Zhirong; Li, Zhenxiang; Duan, Jianchun; Fu, Shuai; Liu, Zhentao; Bai, Hua; Zhang, Zemin; Zhao, Jun; Wang, Xiaodong^*; Wang, Jie

来源：Proceedings of the National Academy of Sciences, 2015, 112(32): 9990-9995.

DOI：10.1073/pnas.1510837112

• epidermal growth factor receptor tyrosine kinase inhibitor
• lung squamous cell carcinoma
• bone morphogenetic proteins
• drug resistance

The empirical criteria for defining a clinical subtype of lung cancer are gradually transiting from histopathology to genetic variations in driver genes. Targeting these driver mutations, such as sensitizing epidermal growth factor receptor (EGFR) mutations, has dramatically improved the prognosis of advanced non-small cell lung cancer (NSCLC). However, the clinical benefit of molecularly targeted therapy on NSCLC appears to be different between lung adenocarcinomas and squamous cell carcinomas (SqCCs). We report here that the resistance of lung SqCC harboring EGFR mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was due to the activation of BMP-BMPR-Smad1/5-p70S6K. The combined treatment of these tumor cells with EGFR-TKI, together with inhibitors specific to BMPR or downstream mTOR, effectively reversed the resistance to EGFR-TKI. Moreover, blocking the whole PI3K-AKTmTOR pathway with the PI3K/mTOR dual inhibitor BEZ235 also showed efficacy in treating this subtype of lung SqCC. This study details the empirical basis for a feasible clinical solution for squamous cell carcinomas with EGFR mutations.

• 出版日期2015-8-11
• 单位北京生命科学研究所; 上海交通大学; 北京大学; 北京市肿瘤防治研究所; 山东省医学科学院