BCR-ABL- and Ras-independent activation of Raf as a novel mechanism of Imatinib resistance in CML

  • Authors: Julia Hentschel, Ignacio Rubio, Melanie Eberhart, Christina Hipler, Jana Schiefner, Katrin Schubert, Ivan F. Loncarevic, Ute Wittig, Aria Baniahmad, Ferdinand von Eggeling
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  • Published online on: Wednesday, June 1, 2011
  • Pages: 585-591
  • DOI: 10.3892/ijo.2011.1062

Abstract

Although the BCR-ABL tyrosine kinase inhibitor Imatinib has undoubtedly revolutionized the therapy of chronic myeloid leukaemia (CML), acquired drug resistance remains a common problem in CML therapy. Resistance often arises from second-line mutations in BCR-ABL or overexpression of the BCR-ABL protein but in ~20% of CML cases resistance mechanisms do not involve altered BCR-ABL function. Imatinib-resistant CML cell lines have been widely used for comparative proteome/genome-wide expression screens in order to decipher resistance mechanisms but a clearcut molecular mechanism or molecular player in BCR-ABL-independent resistance to Imatinib has not yet evolved from those studies. Here, we report the identification of a novel mechanism for Imatinib resistance in CML cells with unaltered BCR-ABL function. Pharmacological analysis evidenced a constitutive, Imatinib-insensitive activation of the Erk-MAPK pathway in resistant cells. A systematic analysis of pathway constituents illustrated that Ras-GTP accumulation remained fully sensitive to Imatinib but c-Raf activity from serum-fed cultures was largely resistant to the drug's action. Sequencing excluded mutations in either B-Raf or c-Raf as the origin of resistance, indicating that a functional alteration in the regulation of c-Raf activity was responsible for this effect. Collectively, these findings highlight a novel mechanism of acquired Imatinib resistance based on the BCR-ABL and Ras-independent constitutive activation of the Erk-MAPK pathway through activated c-Raf, which could prove helpful for a better functional classification of the causes of Imatinib resistance in CML.
Journal Cover

September 2011
Volume 39 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

2012 Impact Factor: 2.773
Ranked #30/202 Oncology
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APA
Hentschel, J., Rubio, I., Eberhart, M., Hipler, C., Schiefner, J., Schubert, K., Loncarevic, I., Wittig, U., Baniahmad, A., & von Eggeling, F. (2011). BCR-ABL- and Ras-independent activation of Raf as a novel mechanism of Imatinib resistance in CML. International Journal of Oncology, 39(3), 585-591.
MLA
Hentschel, Rubio, Eberhart, Hipler, Schiefner, Schubert, Loncarevic, Wittig, Baniahmad, and Ferdinand von Eggeling. "BCR-ABL- and Ras-independent activation of Raf as a novel mechanism of Imatinib resistance in CML." International Journal of Oncology International Journal of Oncology 39.3 (2011): 585-591.
Chicago
Hentschel, Rubio, Eberhart, Hipler, Schiefner, Schubert, Loncarevic, Wittig, Baniahmad, and Ferdinand von Eggeling. "BCR-ABL- and Ras-independent activation of Raf as a novel mechanism of Imatinib resistance in CML." International Journal of Oncology International Journal of Oncology 39 no. 3 (2011): 585-591.