Abstract
10521 Background: Although sunitinib malate has shown significant clinical effect on imatinib-resistant gastrointestinal stromal tumors with acceptable tolerability and improved prognosis for the patients, the mechanism of resistance to the drug is still under investigation. Methods: We analyzed eight pts (7 males, 1 female, median age 59) of 17 pts with imatinib-resistant gastrointestinal stromal tumors treated by sunitinib. Sunitinib was orally administered once a day at a starting dose of 37.5 mg/day, 50 or 75 with 4 wks on and 2 weeks off. Results: All imatinib- as well as sunitinib-resistant lesions showed viable tumor cells strongly re-expressing KIT protein. All pre-imatinib samples had heterogenous KIT mutations either in exon 9 (n=1) or exon 11 (n=7), and seven imatinib-resistant tumors carried secondary mutations either in the ATP-binding domain (n=4) or in the activation loop (n=3) in the same allele as the primary mutation. Pts with resistant tumors carrying secondary mutations purely in the ATP-binding domain obtained clinical benefits from sunitinib, whereas most pts carrying activation loop mutations showed early resistance to the drug. The tumor with mutations in exon 11 and 13 of the KIT gene and showing partial response to sunitinib harbored a third mutation in the activation loop after sunitinib resistance. All additional secondary and tertiary mutations were located in the same allele as the primary mutation (cis-mutation). Conclusions: These findings indicate that imatinib- as well as sunitinib-resistant lesions re-express KIT protein and that additional cis-mutation in the activation loop may be a major cause of sunitinib resistance in gastrointestinal stromal tumor. No significant financial relationships to disclose.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.