title: Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations.
abstract: 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-AKT-mTOR 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.
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China;
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing 102206, China; Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China;
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China; Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong Academy of Medical Sciences, Jinan 250117, China;
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China;
authors.forename: Jianchun
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China;
authors.forename: Shuai
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China;
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China;
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.affiliation: Biodynamic Optical Imaging Center, Integrated Science Research Center, Peking University, Beijing 100871, China.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing 102206, China; Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China; wangxiaodong@nibs.ac.cn wangjie_cc@yahoo.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Beijing Institute for Cancer Research, Beijing 100142, China; wangxiaodong@nibs.ac.cn wangjie_cc@yahoo.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015203:Reproducibility of Results; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D066246:ErbB Receptors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D052004:Bone Morphogenetic Protein Receptors
keywords: bone morphogenetic proteins; drug resistance; epidermal growth factor receptor tyrosine kinase inhibitor; lung squamous cell carcinoma