Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 32, Pages 9990-9995Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1510837112
Keywords
epidermal growth factor receptor tyrosine kinase inhibitor; lung squamous cell carcinoma; bone morphogenetic proteins; drug resistance
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Funding
- Beijing Nova Program from the Beijing Municipal Commission of Science and Technology [xx2014B051, xx2012070]
- National Basic Science 973 from the Chinese Ministry of Science and Technology [2010CB835400, 2012CB837400]
- National Natural Sciences Foundation Key Program [81330062]
- Education Ministry Innovative Research Team Program [IRT13003]
- Fund for Peking University-Tsinghua University Joint Center for Life Sciences Clinical Investigator
- Special Research Foundation of State Key Laboratory of Medical Genomics
- National High Technology Research and Development Program 863 [SS2015AA020403]
- Beijing Technology Project [Z141100000214013]
- Center for Molecular and Translational Medicine
- Collaborative Innovation Center for Cancer Medicine
- Special Research Foundation for the Doctoral Program of Higher Education
- Beijing Excellent Talents Project [2013D003034000019]
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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.
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