PRKX, TTBK2 and RSK4 expression causes sunitinib resistance in kidney carcinoma- and melanoma-cell lines
PRKX, TTBK2 and RSK4 expression causes sunitinib resistance in kidney carcinoma- and melanoma-cell lines
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DOI：
10.1002/ijc.26486
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发表时间：
2012-07-15
影响因子：
6.4
通讯作者：
Ullrich, Axel
中科院分区：
文献类型：
--
作者：
Bender, Claus;Ullrich, Axel
对化疗药物的耐药性是癌症治疗中的一个主要问题。在过去的几年里，多靶点蛋白激酶抑制剂如格列卫、舒尼替尼和索拉非尼在癌症治疗中获得了更广泛的认可。这些药物在体外和患者体内显示出抗肿瘤活性。在治疗中长期使用这些药物通常会导致疾病进展，因为不稳定的癌细胞基因组中的重排和突变积累导致耐药性的形成。然而，产生耐药性的潜在药物特异性机制仍然难以捉摸。因此，详细了解该过程中涉及的分子遗传事件对于抵消舒尼替尼不直接靶向的影响至关重要（未发表的数据）。因此，开发这些激酶的特异性或多靶点抑制剂用于与例如IL-8中和抗体的联合治疗可能会规避或显着延迟舒尼替尼耐药性的形成并增强生存预后。 PRKX、TTBK2 和 RSK4 表达。使用 siRNA 特异性减少这些基因足以使肾脏和黑色素瘤细胞系对舒尼替尼敏感。与 PRKX、TTBK2 或 RSK4 表达升高一致，这种敏化效应在舒尼替尼耐药细胞系中显着更高，表明这些基因基于表达的机制触发舒尼替尼耐药。因此，我们认为 PRKX、TTBK2 和 RSK4 是舒尼替尼治疗中潜在的耐药标记物，因此可能代表开发克服耐药性的新策略的目标。
Resistance to chemotherapeutic agents constitutes a major problem in the treatment of cancer. Over the past years, multi-targeted protein kinase inhibitors such as Gleevec, Sunitinib and Sorafenib are gaining wider acceptance for cancer treatment. These drugs show anti-tumor activity in vitro and in patients. Extended usage of these drugs in therapy commonly results in disease progression due to formation of resistance caused by rearrangements and accumulation of mutations in the unstable cancer cell genome. However, the underlying drug-specific mechanisms for the development of resistance remain elusive. Hence, a detailed understanding of the molecular genetic events involved in this processes is pivotal to counteract are not directly targeted by Sunitinib (unpublished data). Therefore, development of specific or multi-targeted inhibitors for these kinases for combinatorial therapy with e.g., an IL-8 neutralizing antibody might circumvent or substantially delay Sunitinib resistance formation and enhance survival prognosis. PRKX, TTBK2 and RSK4 expression. The specific reduction of these genes employing siRNA was sufficient to sensitize the kidney- and melanoma-cell lines against Sunitinib. In line with the elevated expression of PRKX, TTBK2 or RSK4, this sensitization effect was strikingly higher in the Sunitinib resistant cell lines, suggesting an expression-based mechanism of these genes to trigger Sunitinib resistance. Hence, we propose that PRKX, TTBK2 and RSK4 are potential resistance markers in Sunitinib therapy and might therefore represent targets for the development of novel strategies to overcome resistance.