Oncol Res Treat. 2017;40(7-8):435-439. doi: 10.1159/000475503. Epub 2017 Jun 20.
Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established. To this end, we conducted a post-hoc biomarker analysis of tumor samples from non-small cell lung cancer (NSCLC) patients treated with the PLK1 inhibitor BI2536 in a phase II study.
We analyzed formalin-fixed paraffin-embedded surplus tumor tissue from 47 study patients using immunohistochemistry (IHC) and DNA sequencing of KRAS, EGFR, BRAF, and PIK3CA.
KRAS-mutated patients showed numerically prolonged progression-free survival, but statistical significance was not established. Interestingly, when pathways rather than single genes were analyzed, a positive correlation between IHC staining of activated ERK (p-ERK) and mutated KRAS was detected, whereas KRAS mutation status was found to be negatively correlated with activated AKT (p-AKT).
With this hypothesis-generating study in BI2531-treated patients, we could not establish a correlation between KRAS mutations and relevant clinical endpoints. Future clinical trials with concomitant systematic biosampling and comprehensive molecular analyses are required to identify biomarkers predictive for response to PLK1 inhibitors.
丝氨酸/苏氨酸激酶 Polo 样激酶 1（PLK1）在肿瘤中经常过表达，因此被视为各种癌症中有前途的治疗靶点。最近已经开发出几种 PLK1 抑制剂，并在实体瘤中进行了临床测试，但成功率有限。到目前为止，尚未建立用于 PLK1 抑制剂的预测性生物标志物。为此，我们对接受 PLK1 抑制剂 BI2536 治疗的 II 期研究中的非小细胞肺癌（NSCLC）患者的肿瘤样本进行了基于事后的生物标志物分析。
我们使用免疫组织化学（IHC）和 KRAS、EGFR、BRAF 和 PIK3CA 的 DNA 测序分析了 47 名研究患者的福尔马林固定石蜡包埋的剩余肿瘤组织。
KRAS 突变患者的无进展生存期有延长的趋势，但未达到统计学意义。有趣的是，当分析途径而不是单个基因时，检测到激活 ERK（p-ERK）的 IHC 染色与突变的 KRAS 之间存在正相关，而 KRAS 突变状态与激活的 AKT（p-AKT）呈负相关。
通过对接受 BI2531 治疗的患者进行这项假设生成研究，我们无法确定 KRAS 突变与相关临床终点之间的相关性。需要进行具有系统生物样本采集和全面分子分析的未来临床试验，以确定预测对 PLK1 抑制剂反应的生物标志物。
