Chromosomal instability determines taxane sensitivity - supplementary materials

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.

微管稳定（Microtubule-stabilizing, MTS）剂（如紫杉烷类）是一类重要的化疗药物，但其具体作用机制尚未完全阐明。我们在多种细胞系中筛选出一组响应MTS剂时表达被抑制的基因，并观察到这些基因在表现出染色体不稳定（chromosomal instability, CIN）的肿瘤中存在过表达现象。对这50个基因中的22个进行沉默实验后发现，其中多数基因参与DNA修复过程，可导致癌细胞死亡，这提示这些基因与非整倍体细胞的存活密切相关。这些“CIN存活基因”的过表达与雌激素受体阳性乳腺癌患者的不良预后相关，且在基底样型及人表皮生长因子受体2（Her2）阳性的乳腺癌病例中频繁出现。在二倍体细胞（而非染色体不稳定细胞）中，紫杉醇可抑制CIN存活基因的表达，随后引发细胞死亡。在OV01卵巢癌临床试验中，高水平CIN与紫杉烷耐药性相关，但与卡铂敏感性正相关，这表明CIN或可在体内决定机体对MTS剂的应答反应。因此，治疗前对CIN水平进行评估，或可优化此类药物的治疗分层策略及相关临床试验设计。