PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance
PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance
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DOI：
10.1038/s41467-020-17697-1
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发表时间：
2020-08-13
影响因子：
16.6
通讯作者：
Marangoni, Elisabetta
中科院分区：
文献类型：
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作者：
Montaudon, Elodie;Nikitorowicz-Buniak, Joanna;Marangoni, Elisabetta
雌激素受体（ER）阳性乳腺癌（BC）患者很大一部分会产生对内分泌治疗（ET）的抗性，并通过转移性疾病复发。在这里，我们对匹配的原发性乳腺肿瘤和骨转移的患者衍生异种移植（PDX）进行了整个外显子组测序和基因表达分析。转录组分析表明，PDX中G2/M检查点的富集和Polo样激酶1（PLK1）的上调。 PLK1抑制作用导致高度增殖的CCND1驱动的PDX的肿瘤收缩，其中包括具有获得的palbociclib耐药性的不同RB阳性PDX。在内分泌耐药细胞系中的机械研究表明，PLK1在调节细胞增殖中的非ER非依赖性功能。最后，在ER阳性BC的两个独立的临床队列中，我们发现PLK1的高表达与短转移酶的生存率和对Anastrozole的反应不佳之间存在很强的关联。总之，我们的发现支持晚期CCND1驱动的BC患者PLK1抑制剂的临床发育，包括在palbociclib治疗方面进展。
A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment.