Soverini Simona, Colarossi Sabrina, Gnani Alessandra, Castagnetti Fausto, Rosti Gianantonio, Bosi Costanza, Paolini Stefania, Rondoni Michela, Piccaluga Pier Paolo, Palandri Francesca, Giannoulia Panagiota, Marzocchi Giulia, Luatti Simona, Testoni Nicoletta, Iacobucci Ilaria, Cilloni Daniela, Saglio Giuseppe, Baccarani Michele, Martinelli Giovanni
Institute of Hematology and Medical Oncology L. e A. Seràgnoli, University of Bologna, Bologna, Italy.
Haematologica. 2007 Mar;92(3):401-4. doi: 10.3324/haematol.10822.
The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
费城染色体阳性（Ph+）白血病患者对Bcr-Abl抑制剂甲磺酸伊马替尼产生耐药性，促使了对几种伊马替尼不敏感的Bcr-Abl突变形式具有活性的第二代化合物的研发，包括达沙替尼（BMS-354825；百时美施贵宝公司）。为了评估哪些预先存在的或新出现的激酶结构域突变与达沙替尼临床疗效降低相关，我们分析了21例在达沙替尼治疗期间无反应或复发的Ph+患者治疗前和治疗期间的BCR-ABL激酶序列。在除1例患者之外的所有患者中，均发现对达沙替尼耐药总是与315位残基和/或317位残基的突变相关。
