title: MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Department of Ophthalmology National Key Discipline of Pediatrics (Capital Medical University) Ministry of Education Beijing Children's Hospital Capital Medical University Beijing China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Department of Emergency Medicine Qingdao Municipal Hospital Qingdao China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yang
authors.affiliation: The University of Texas School of Public Health Houston Texas USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences Zhongguancun Life Science Park Beijing China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: The Department of Medical Oncology Cancer Hospital Chinese Academy of Medical Sciences Beijing China.
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.affiliation: The Department of Medical Oncology Cancer Hospital Chinese Academy of Medical Sciences Beijing China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
keywords: Bevacizumab; MEK inhibitor; connexin; non‐small‐cell lung cancer; resistance