Cancer Res.:揭示卵巢癌获得性耐药机制

澳大利亚墨尔本的彼得麦卡勒姆癌症中心的癌症基因组学和遗传研究组负责人David Bowtell博士，和他的同事利用肿瘤样本进行研究，首次报道了高度恶性浆液性卵巢癌化疗耐药性的机制。

"高度恶性浆液性癌约占上皮侵入性卵巢癌死亡率的三分之二"Bowtell说，"我们试图发现从患者第一次接受手术和化疗，到肿瘤复发并最终发展为抵抗化疗，这一过程中的分子变化。"

研究人员分析了个别病人转移病灶和22例配对的治疗前和治疗后的肿瘤样本，检测其中的空间和时间的基因变异。

结果发现，最经常发生的基因变化是LRP1B基因的缺失和/或下调。该基因编码一个蛋白质家族成员，负责运输脂类进入细胞。为了进一步验证他们的研究结果，研究人员采用遗传工程手段在卵巢癌细胞株中表达或敲除LRP1B基因，从而研究获得或丢失该基因的影响。 LRP1B基因的丢失导致，接受药物治疗的妇女对化疗药脂质体阿霉素的抵抗。

编译自Mechanisms of acquired chemoresistance in ovarian cancer identified

doi:10.1016/j.cell.2011.10.017
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LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin

Prue A. Cowin1,3,4,Joshy George1,5,Sian Fereday1,Elizabeth Loehrer1,Peter Van Loo6,7,Carleen Cullinane1,4,Dariush Etemadmoghadam1,4,Sarah Ftouni1,Laura Galletta1,Michael S. Anglesio8,Joy Hendley1,Leanne Bowes1,Karen E. Sheppard2,5,Elizabeth L. Christie1,Australian Ovarian Cancer Study1,9,11,Richard B. Pearson2,3,5,Paul R. Harnett10,Viola Heinzelmann-Schwarz12,Michael Friedlander13,Orla McNally14,Michael Quinn14,Peter Campbell6,Anna deFazio9, andDavid D.L. Bowtell1,3,4,5

 High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.