CTNNB1（β-连环蛋白）突变型前列腺癌的罕见组织学转化伴侵袭性临床病程。
Rare histologic transformation of a CTNNB1 (β-catenin) mutated prostate cancer with aggressive clinical course.
机构信息
Department for BioMedical Research, University of Bern, Bern, 3008, Switzerland.
Department of Medical Oncology, Inselspital, University Hospital of Bern, Bern, 3010, Switzerland.
出版信息
Diagn Pathol. 2024 Jun 21;19(1):83. doi: 10.1186/s13000-024-01511-3.
BACKGROUND
Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking.
METHODS
We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays.
RESULTS
Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor.
CONCLUSIONS
The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.
背景
连环蛋白（钙黏蛋白相关蛋白）β 1（CTNNB1）基因改变在前列腺癌（PCa）中罕见。功能获得性突变导致β-连环蛋白过表达，继而导致 Wnt/β-连环蛋白信号通路过度激活，与 PCa 的进展和治疗耐药有关。迄今为止，针对 Wnt/β-连环蛋白驱动的 PCa，尚无成功的靶向治疗选择。
方法
我们报告了一例 CTNNB1（β-连环蛋白）突变转移性去势抵抗性前列腺癌（mCRPC）的罕见组织学转化，该病例临床上表现为侵袭性疾病过程。我们对肝转移瘤标本进行了组织学和分子特征分析，并成功地从肝转移灶中生成了患者来源的类器官（PDOs）和患者来源的异种移植（PDX）。我们使用生成的细胞模型进行了进一步的分子特征分析和药物反应测定。
结果
肝转移活检和 PDX 肿瘤的免疫组化显示缺乏典型 PCa（如 AR、PSA、PSAP、ERG）或神经内分泌标志物（突触素）的表达，符合双阴性 CRPC，但核β-连环蛋白表达、角蛋白 7 和 34βE12 阳性。荧光原位杂交（FISH）证实存在 ERG 重排。药物反应测定证实，与临床疾病过程一致，对 mCRPC 中常用药物（如恩扎卢胺、多西他赛）缺乏敏感性。酪蛋白激酶 1（CK1）抑制剂 IC261 和 tankyrase 1/2 抑制剂 G700-LK 表现出适度的活性。此外，尽管存在 CTNNB1 突变，PDOs 对 SMARCA2/4 靶向 PROTAC 降解剂和抑制剂的敏感性较低。
结论
报告的 CTNNB1 突变 mCRPC 病例强调了双阴性 CRPC 诊断的潜在挑战，并强调了进一步转化研究的相关性，以实现对 mCRPC 罕见分子亚型的成功靶向治疗。
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