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Thorac Cancer. 2016 Apr 26;7(3):279-87. doi: 10.1111/1759-7714.12325. Epub 2015 Dec 16.

MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation.

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The Department of Ophthalmology National Key Discipline of Pediatrics (Capital Medical University) Ministry of Education Beijing Children's Hospital Capital Medical University Beijing China.
The Department of Emergency Medicine Qingdao Municipal Hospital Qingdao China.
The Department of Thoracic Medical Oncology Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Peking University Cancer Hospital & Beijing Institute for Cancer Research Beijing China.
The University of Texas School of Public Health Houston Texas USA.
National Institute of Biological Sciences Zhongguancun Life Science Park Beijing China.
The Department of Medical Oncology Cancer Hospital Chinese Academy of Medical Sciences Beijing China.



Bevacizumab (BV) is broadly used to treat a number of cancers; however, BV resistance mechanisms and strategies to overcome this resistance are yet to be determined.


We established xenograft mice models harboring Kirsten rat sarcoma oncogene homolog (KRAS) mutations based on the A549 cell line, and tested the responses of xenograft tumors to a series of drugs in ex vivo and in vivo experiments. Changes in transcriptive level were analyzed by ribonucleic acid (RNA) sequencing and the expressions of connexins were determined by immunohistochemistry staining.


A549 cell mutation type (KRAS G12S) was confirmed by sequencing. After treating the xenograft tumors with BV, the median interval time from BV administration to tumor volume more than 2.5-fold of the original was 37 days, compared with 21 days in the control (P = 0.025). A549 cells showed resistantance to selumitinib (MEK inhibitor) but were sensitive to selumitinib plus BEZ235 (phosphoinositide 3-kinase/mammalian target of rapamycin dual inhibitor). However, selumitinib could effectively reverse the resistance to BV in in vivo experiments. RNA sequencing showed that mouse genes, but not human genes, activated the mitogen-activated protein kinase signaling pathway, accompanied by activation of the Wnt and Hedgehog pathways. Connexin43 (S261) was phosphorylated before and during BV treatment, and subsequently transitioned to negative phosphorylated-connexin 43-S261 after resistance to BV.


Combining an MEK inhibitor with BV was a potential strategy to reverse initial BV resistance. Phosphorylated-connexin 43 might be associated with the response to BV.


Bevacizumab; MEK inhibitor; connexin; non‐small‐cell lung cancer; resistance

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