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Wang Y, Yan P, Liu Z, et al. MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation. Thorac Cancer. 2015;7(3):279-87doi: 10.1111/1759-7714.12325.
Wang, Y., Yan, P., Liu, Z., Yang, X., Wang, Y., Shen, Z., Bai, H., Wang, J., & Wang, Z. (2016). MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation. Thoracic cancer, 7(3), 279-87. https://doi.org/10.1111/1759-7714.12325
Wang, Yuan, et al. "MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation." Thoracic cancer vol. 7,3 (2016): 279-87. doi: https://doi.org/10.1111/1759-7714.12325
Wang Y, Yan P, Liu Z, Yang X, Wang Y, Shen Z, Bai H, Wang J, Wang Z. MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation. Thorac Cancer. 2016 Apr 26;7(3):279-87. doi: 10.1111/1759-7714.12325. Epub 2015 Dec 16. PMID: 27148412; PMCID: PMC4846615.
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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.

Thoracic cancer

Yuan Wang, Ping Yan, Zhentao Liu, Xiaodan Yang, Yaping Wang, Zhirong Shen, Hua Bai, Jie Wang, Zhijie Wang

Affiliations

  1. The Department of Ophthalmology National Key Discipline of Pediatrics (Capital Medical University) Ministry of Education Beijing Children's Hospital Capital Medical University Beijing China.
  2. The Department of Emergency Medicine Qingdao Municipal Hospital Qingdao China.
  3. 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.
  4. The University of Texas School of Public Health Houston Texas USA.
  5. National Institute of Biological Sciences Zhongguancun Life Science Park Beijing China.
  6. The Department of Medical Oncology Cancer Hospital Chinese Academy of Medical Sciences Beijing China.

PMID: 27148412 PMCID: PMC4846615 DOI: 10.1111/1759-7714.12325

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.

CONCLUSION: 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.

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

References

  1. Cancer Res Treat. 2014 Jan;46(1):48-54 - PubMed
  2. BMC Gastroenterol. 2015 Mar 24;15:37 - PubMed
  3. J Clin Invest. 2011 Apr;121(4):1313-28 - PubMed
  4. Cell. 2009 Mar 6;136(5):839-51 - PubMed
  5. N Engl J Med. 2010 Jun 24;362(25):2380-8 - PubMed
  6. Nat Rev Clin Oncol. 2011 May 31;8(7):393-404 - PubMed
  7. Semin Cancer Biol. 2004 Apr;14(2):93-104 - PubMed
  8. J Clin Oncol. 2004 Jun 1;22(11):2184-91 - PubMed
  9. Lancet Oncol. 2012 Mar;13(3):239-46 - PubMed
  10. Clin Cancer Res. 2006 Sep 1;12(17):5018-22 - PubMed
  11. J Natl Cancer Inst. 1990 Jan 3;82(1):4-6 - PubMed
  12. Lancet Oncol. 2010 Feb;11(2):121-8 - PubMed
  13. Future Oncol. 2014 Jun;10(8):1417-25 - PubMed
  14. Cancer. 2012 Jul 15;118(14):3455-67 - PubMed
  15. J Clin Oncol. 2009 Mar 10;27(8):1227-34 - PubMed
  16. Lancet Oncol. 2011 Aug;12(8):735-42 - PubMed
  17. Biochimie. 2013 Jun;95(6):1110-9 - PubMed
  18. N Engl J Med. 2009 Sep 3;361(10):947-57 - PubMed
  19. Nat Rev Cancer. 2010 Aug;10(8):587-93 - PubMed

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