A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors
| Autor: | Jonathan C. Trent, Kimberly Hayes, A. K. Raymond, Victor G. Prieto, Marco A. De Velasco, Shreyaskumar Patel, Elsie F. Wu, Robert S. Benjamin, Michael A. Burgess, Marsha L. Frazier, Walter N. Hittelman, Barry W. Feig, Caroline O. Oyedeji, Lei L. Chen, Wei Zhang, Raphael E. Pollock, Homer A. Macapinlac, Kelly K. Hunt, Gregory N. Fuller, Haesun Choi, Latha Ramdas |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
medicine.drug_class Mutation Missense Antineoplastic Agents Piperazines Tyrosine-kinase inhibitor hemic and lymphatic diseases medicine Humans Missense mutation Stromal tumor neoplasms Alleles Gastrointestinal Neoplasms Randomized Controlled Trials as Topic ABL Base Sequence biology Imatinib Exons digestive system diseases Protein Structure Tertiary Proto-Oncogene Proteins c-kit Pyrimidines Imatinib mesylate Clinical Trials Phase III as Topic Oncology Drug Resistance Neoplasm Benzamides Disease Progression Imatinib Mesylate biology.protein Cancer research Stromal Cells Tyrosine kinase Platelet-derived growth factor receptor medicine.drug |
| Zdroj: | Cancer Research. 64:5913-5919 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-04-0085 |
| Popis: | KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|