Mancini Manuela, Brusa Gianluca, Zuffa Elisa, Corrado Patrizia, Martinelli Giovanni, Grafone Tiziana, Barbieri Enza, Santucci Maria Alessandra
Istituto di Ematologia e Oncologia Medica "Lorenzo e Ariosto Seràgnoli", University of Bologna-Medical School, Via Massarenti 9, 40138-Bologna, Italy.
Leuk Res. 2007 Jul;31(7):979-87. doi: 10.1016/j.leukres.2006.09.022. Epub 2006 Nov 28.
Complementary inhibition of tyrosine and SRC kinases implement dual SRC/ABL inhibitor effects in chronic myeloid leukemia (CML). Here, we show that one such inhibitor, SKI-606, induces persistent Cdk2 inactivation leading to growth arrest of BCR-ABL-expressing cells either IM-sensitive or driven to IM-resistance by other events than gene overexpression and point mutations. Inhibition of Akt serine/threonine kinase, a phosphatidylinositol 3 kinase (PI-3k) target that integrates p210 TK signaling with membrane-associated SRC kinases, is a central component of restored expression and subcellular redistribution of Cdk2 regulatory signals (p21 and p27 and Cdc25A phosphatase) in response to SKI-606. The putative roles of growth factor (namely IL-3) autocrine loop in BCR-ABL-expressing progenitor progression towards a drug-resistant phenotype are discussed.
酪氨酸激酶和SRC激酶的互补抑制在慢性粒细胞白血病（CML）中实现了双重SRC/ABL抑制剂效应。在此，我们表明，一种这样的抑制剂SKI-606可诱导持续的Cdk2失活，导致表达BCR-ABL的细胞生长停滞，这些细胞对伊马替尼（IM）敏感，或因基因过表达和点突变以外的其他事件而对IM产生耐药性。抑制Akt丝氨酸/苏氨酸激酶是恢复Cdk2调节信号（p21、p27和Cdc25A磷酸酶）表达和亚细胞重新分布以响应SKI-606的核心组成部分，Akt丝氨酸/苏氨酸激酶是一种磷脂酰肌醇3激酶（PI-3k）靶点，它将p210 TK信号与膜相关SRC激酶整合在一起。讨论了生长因子（即白细胞介素-3）自分泌环在表达BCR-ABL的祖细胞向耐药表型进展中的假定作用。
