Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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高度浆液性卵巢癌中ALDH1A1相关的干性是阴性的预后指标，但可能被EGFR / mTOR-PI3K /极光激酶抑制剂靶向。

化疗反应不良仍然是高级别浆液性卵巢癌（HGSC）的主要治疗挑战。癌症干细胞是复发和治疗失败的主要因素，因为它们可以在常规治疗中存活下来。我们的目标是表征原发于患者的细胞系中的干性特征，将干性标志物与临床结果相关联，并测试我们的细胞对常规药物和探索性药物的反应。前瞻性和/或在新辅助化疗后收集组织和腹水样品。测试在有利于贴壁或球状生长的条件下培养的原代癌细胞的干性标记；在组织中分析了相同的标志物，并将其与化疗反应和生存相关。用306种肿瘤药物进行了药物敏感性和耐药性测试。与贴壁生长条件细胞相比，球状生长条件HGSC细胞显示出干细胞标志物表达增加（包括醛脱氢酶同工型I； ALDH1A1），并增加了对铂和紫杉烷的抗性。一组八个干性标记将未经治疗的肿瘤分为两个簇，并鉴定了具有丰富干性特征的HGSC的一个独特亚组。新辅助化疗后，ALDH1A1的表达增加，但大多数其他干性标记却没有增加，并且其在未治疗的肿瘤中的表达与化学抗性相关，并降低了生存率。在药物敏感性和耐药性测试中，包括两种PI3K-mTOR抑制剂在内的五种化合物在两种细胞培养条件下均表现出显着的活性。包括EGFR，PI3K-mTOR和Aurora激酶抑制剂在内的13种化合物对球状细胞的毒性比对贴壁细胞的毒性更大。我们的研究结果确定了HGSC中的干性标记，如果通过未经治疗的肿瘤表达，则干性标记与对常规化学疗法的反应降低以及生存期降低相关。EGFR，mTOR-PI3K和极光激酶抑制剂是靶向此细胞群体的候选药物。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 mTOR-PI3K和极光激酶抑制剂是靶向该细胞群体的候选药物。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 mTOR-PI3K和极光激酶抑制剂是靶向该细胞群体的候选药物。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版