Ranganathan Parvathi, Kashyap Trinayan, Yu Xueyan, Meng Xiaomei, Lai Tzung-Huei, McNeil Betina, Bhatnagar Bhavana, Shacham Sharon, Kauffman Michael, Dorrance Adrienne M, Blum William, Sampath Deepa, Landesman Yosef, Garzon Ramiro
The Ohio State University, Columbus, Ohio.
Karyopharm Therapeutics Inc, Newton, Massachusetts.
Clin Cancer Res. 2016 Dec 15;22(24):6142-6152. doi: 10.1158/1078-0432.CCR-15-2885. Epub 2016 Jun 29.
Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore, we asked whether adding already established effective drugs such as topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML.
The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML.
Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared with each single therapy.
Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of patients with AML that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC-dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. Clin Cancer Res; 22(24); 6142-52. ©2016 AACR.
塞利尼索是一种XPO1的选择性抑制剂，目前正在急性髓系白血病（AML）的临床试验中作为单一药物进行测试。然而，考虑到AML的分子复杂性，单药治疗不太可能治愈AML。因此，我们探讨了将拓扑异构酶（Topo）II抑制剂等已证实有效的药物与塞利尼索联合使用是否会增强其对AML的抗白血病作用。
在已建立的AML细胞和动物模型中评估了使用Topo II抑制剂（伊达比星、柔红霉素、米托蒽醌、依托泊苷）和塞利尼索联合药物治疗的疗效。
塞利尼索与Topo II抑制剂联合治疗在AML细胞系和患者样本中产生了治疗协同作用。使用异种移植MV4-11 AML小鼠模型，我们发现与单一疗法相比，塞利尼索和伊达比星联合治疗显著延长了白血病小鼠的生存期。
Topo IIα异常的核输出和细胞质定位已被确定为导致癌症耐药的机制之一。在此，我们表明，在一部分表达细胞质Topo IIα的AML患者中，塞利尼索治疗导致Topo IIα蛋白的核保留，从而增加了对伊达比星的敏感性。塞利尼索治疗AML细胞导致c-MYC依赖性地降低DNA损伤修复基因（Rad51和Chk1）的mRNA和蛋白表达，随后抑制同源重组修复并增加对Topo II抑制剂的敏感性。本文报道的临床前数据支持进一步开展使用塞利尼索和Topo II抑制剂联合治疗AML的临床研究。《临床癌症研究》；22(24)；6142 - 52。©2016美国癌症研究协会。
