Chromosomal instability determines taxane response
Chromosomal instability determines taxane response
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DOI：
10.1073/pnas.0811835106
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发表时间：
2009-05-26
影响因子：
11.1
通讯作者：
Downward, Julian
中科院分区：
文献类型：
--
作者：
Swanton, Charles;Nicke, Barbara;Downward, Julian
微管稳定 (MTS) 药物，如紫杉烷类，是重要的化疗药物，但其作用机制尚不清楚。我们鉴定了一组在 MTS 药物作用下在多个细胞系中受到抑制的基因，并观察到这些基因在表现出染色体不稳定 (CIN) 的肿瘤中过度表达。其中 22/50 的基因（其中许多与 DNA 修复有关）沉默会导致癌细胞死亡，这表明这些基因与非整倍体细胞的存活有关。这些“CIN 存活”基因的过度表达与雌激素受体阳性乳腺癌的不良预后相关，并且经常发生在基底细胞样和 Her2 阳性病例中。在二倍体细胞中，但在染色体不稳定的细胞中，紫杉醇不会抑制 CIN 存活基因，随后导致细胞死亡。在 OV01 卵巢癌临床试验中，高水平的 CIN 与紫杉烷耐药性相关，但与卡铂敏感性相关，表明 CIN可以确定 MTS 体内反应，因此，CIN 的治疗前评估可以优化使用这些药物的治疗分层和临床试验设计。
Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these "CIN-survival'' genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.