Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Leukemia. 2010 Dec;24(12):2100-9. doi: 10.1038/leu.2010.212. Epub 2010 Sep 16.
Drug resistance is a growing concern with clinical use of tyrosine kinase inhibitors. Utilizing in vitro models of intrinsic drug resistance and stromal-mediated chemoresistance, as well as functional mouse models of progressive and residual disease, we attempted to develop a potential therapeutic approach designed to suppress leukemia recurrence following treatment with selective kinase inhibitors. The novel IAP inhibitor, LCL161, [corrected] was observed to potentiate the effects of tyrosine kinase inhibition against leukemic disease both in the absence and presence of a stromal-protected [corrected] environment. LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. In addition, LCL161 synergized in vivo with nilotinib to reduce leukemia burden significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib. Finally, LCL161 displayed antiproliferative effects against cells characterized by intrinsic resistance to tyrosine kinase inhibitors as a result of expression of point mutations in the protein targets of drug inhibition. These results support the idea of using IAP inhibitors in conjunction with targeted tyrosine kinase inhibition to override drug resistance and suppress or eradicate residual disease.
耐药性是临床应用酪氨酸激酶抑制剂日益关注的问题。利用内在耐药性和基质介导的化疗耐药性的体外模型，以及进行性和残留疾病的功能性小鼠模型，我们试图开发一种潜在的治疗方法，旨在抑制治疗后选择激酶抑制剂的白血病复发。新型 IAP 抑制剂 LCL161 [已更正]被观察到增强了酪氨酸激酶抑制对白血病的作用，无论是在没有基质保护 [已更正]环境的情况下，还是在存在基质保护 [已更正]环境的情况下。LCL161 增强了 nilotinib 和 PKC412 的促凋亡作用，在体外对白血病具有活性，并增强了两种激酶抑制剂在体内对白血病的活性。此外，LCL161 在体内与 nilotinib 协同作用，使白血病负担显著低于中度至高剂量 nilotinib 抑制所达到的基线水平。最后，LCL161 对因药物抑制的靶蛋白点突变而表现出内在耐药性的细胞表现出抗增殖作用。这些结果支持使用 IAP 抑制剂与靶向酪氨酸激酶抑制联合使用以克服耐药性并抑制或根除残留疾病的观点。
