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Dasatinib (Sprycel), formerly BMS-354825
Dasatinib (brand name Sprycel), formerly known as BMS-354825, has been developed by Bristol-Myers Squibb. It is a potent oral multi-kinase inhibitor that targets ABL, SRC, KIT, PDGFR, and other tyrosine kinases. It has achieved success in clinical trials for imatinib-resistant patients with leukemia. Dasatinib was approved by the FDA on 6/28/2006 for use in those patients with chronic myeloid leukemia or acute lymphoblastic leukemia who have developed resistance or intolerance to imatinib (Gleevec). You can read about Sprycel's FDA approval for leukemia at the FDA site.
Dasatinib is structurally unrelated to imatinib, possibly demonstrating a higher binding affinity to KIT, regardless of the conformation of the KIT activation loop. It inhibits KIT autophosphorylation and KIT-dependent activation of downstream pathways including RAS/MAPK, PI3K/AKT, and STAT3. Preclinical cell studies by Shah et al (2006) indicate that dasatinib may inhibit the KIT D816V mutation that is resistant to imatinib. Shah et al suggest dasatinib may therefore be useful in treating systemic mastocytosis. Additional preclinical studies by Schittenhelm et al (2006) indicate effectiveness against KIT activation loop mutations D816Y and D116F as well as D816V. Therefore, dasatinib may potentially be useful against imatinib-resistant GISTs harboring these certain activation-loop mutations.
Some GIST patients have enrolled in a clinical trial testing dasatinib in solid tumors. No results are available yet. To read about this trial, link to clinicatrials.gov.
For a lay-language summary about KIT inhibition and dasatinib, link to Eurekalert.
