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Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor

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Abstract

Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the GI tract and one of the most common sarcomas, is dependent on the expression of the mutated KIT or platelet-derived growth factor receptor in most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by directly binding into the ATP-binding pocket of the kinase.  It is becoming increasingly apparent that the binding affinity of imatinib for the receptor   is dependent on the type and location of mutation.  Within KIT, patients whose tumor has an exon 9 mutation are treated by many clinicians with higher doses of imatinib than those patients with mutations within exon 11. Additionally, there are over 400 unique mutations within exon 11 that may have distinctly different binding affinity for imatinib as well as other kinases. Secondary KIT mutations generally occur at a codon where imatinib binds resulting in KIT reactivation and resistance. Sunitinib malate, a second-generation KIT inhibitor is active in imatinib-resistant disease and is FDA-approved for use in this setting. In this review, we describe the biology of the genes and gene mutations responsible for GIST and discuss known and potential clinical implications.

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Acknowledgments

Logistical support during submission of this article was provided by Springer Healthcare LLC. This support was funded by Novartis.

Conflict of interest

Wei-Lein Wang: No conflicts to report; Anthony Conley: No conflicts of interest; Suzanne George: Novartis Advisory Board and Clinical Trial Support; Pfizer Advisory Board and Clinical Trial Support; Alexander Lazar: Novartis speaker bureau and equity position holder in Novartis; Laura Nolden: No conflicts of interest; David Reynoso: No conflicts of interest; Jonathan Trent: Novartis Advisory Board, Honoraria, and Clinical Trial Support; Merck Grant Support.

Author information

Authors and Affiliations

  1. Departments of Pathology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

    Wei-Lien Wang & Alexander J. Lazar

  2. Department of Sarcoma Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

    Anthony Conley, David Reynoso, Laura Nolden & Jonathan C. Trent

  3. Dana-Farber Cancer Institute, Center for Soft-Tissue and Bone Oncology, Boston, MA, USA

    Suzanne George

Authors
  1. Wei-Lien Wang
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  2. Anthony Conley
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  3. David Reynoso
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  4. Laura Nolden
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  5. Alexander J. Lazar
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  6. Suzanne George
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  7. Jonathan C. Trent
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Corresponding author

Correspondence to Jonathan C. Trent.

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Wang, WL., Conley, A., Reynoso, D. et al. Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor. Cancer Chemother Pharmacol 67 (Suppl 1), 15–24 (2011). https://doi.org/10.1007/s00280-010-1513-8

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  • DOI: https://doi.org/10.1007/s00280-010-1513-8

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