文章：

芳香酶抑制剂耐药机制

Mechanisms of aromatase inhibitor resistance

原文发布日期：2015-04-25

DOI: 10.1038/nrc3920

类型: Review Article

开放获取: 否

要点：

1. Aromatase inhibitors (AIs) are frequently prescribed for patients with oestrogen receptor-positive (ER⁺) breast cancer to control advanced disease and to prevent relapse after treatment with localized breast cancer (adjuvant therapy). However, resistance to AI therapy is common, occurring in over 20% of patients with early-stage disease and is inevitable in patients with metastatic disease.
2. Resistance to AI therapy can be detected in primary tumours by measuring on-treatment tumour Ki67 expression. The idea of monitoring tumour Ki67 expression as a clinical tool is being prospectively evaluated for individualized treatment approaches that de-escalate therapy for responsive tumours (Ki67^low after AI treatment) and escalate therapy for unresponsive tumours (Ki67^high after treatment).
3. Genomic analyses of ER⁺ tumours have identified more than 30 significantly mutated genes the role of which in AI therapy responsiveness is under investigation. To date, TP53 has been associated with high levels of Ki67 both before and after therapy, and therefore with more aggressive disease, and MAP3K1 has the opposite pattern, and is therefore associated with more indolent disease. GATA3 mutation was associated with a greater fall in Ki67 expression with treatment, suggesting that GATA3-mutant tumours are more dependent on oestrogen than GATA3 wild-type tumours.
4. ERα ligand-binding domain mutations emerge after prolonged periods of AI therapy and are therefore an acquired resistance mechanism to AI therapy. Other genomic aberrations in the ESR1 locus have also been identified, including translocations, amplifications and localized gene rearrangements within the long arm of chromosome 6. The frequency of these findings in AI-resistant tumours and their role in AI resistance is under investigation.
5. Cancer cell-intrinsic mechanisms for AI resistance include loss of ER expression, upregulation of growth factor receptor pathways including the ERBB family of receptors, fibroblast growth factor receptor (FGFR), insulin-like growth factor 1 receptor (IGF1R) and their downstream signalling including MAPK and PI3K–AKT–mTOR, deregulation of apoptosis and cell cycle machinery.
6. Cancer cell-extrinsic mechanisms depend on interactions with other cell types within the tumour microenvironment (fibroblasts, immune cells, adipose cells and mesenchymal stem cells) that collectively orchestrate the development and maintenance of AI resistance.
7. Mechanism-based inhibitors against cyclin-dependent kinase 4 (CDK4) and CDK6, PI3K and histone deacetylases are among the most promising strategies being tested to overcome AI resistance in Phase III clinical trials.
8. Further advances in our understanding of AI-resistance mechanisms rely on prospective longitudinal studies of tumour samples collected at multiple disease time points and also on preclinical models that capture the full spectrum and biology of AI-resistance mechanisms.

要点翻译：

1. 芳香化酶抑制剂（AIs）常被开给雌激素受体阳性（ER+）乳腺癌患者，用于控制晚期病情及预防局部乳腺癌治疗后的复发（辅助治疗）。然而，AI治疗耐药现象十分普遍，超过20%的早期患者会出现耐药，而转移性患者则必然产生耐药性。
2. 通过测量治疗期间肿瘤Ki67表达水平，可在原发肿瘤中检测到AI治疗耐药性。目前正在前瞻性评估将肿瘤Ki67表达监测作为临床工具的理念，旨在实现个体化治疗——对治疗反应良好的肿瘤（AI治疗后Ki67低表达）采取降阶梯治疗，而对治疗无反应的肿瘤（AI治疗后Ki67高表达）采取升阶梯治疗。
3. 对ER+肿瘤的基因组分析已识别出30多个显著突变基因，这些基因在AI治疗反应中的作用正在研究中。迄今发现，TP53基因与治疗前后高水平的Ki67相关，因此与更具侵袭性的疾病相关；而MAP3K1则呈现相反模式，与惰性病程相关。GATA3突变与治疗后Ki67表达显著下降相关，表明GATA3突变型肿瘤比GATA3野生型肿瘤更依赖雌激素。
4. ERα配体结合域突变在长期AI治疗后出现，因此是AI治疗的获得性耐药机制。ESR1基因座的其他基因组异常也已被发现，包括6号染色体长臂内的易位、扩增和局部基因重排。这些发现在AI耐药肿瘤中的频率及其在AI耐药中的作用正在研究中。
5. 癌细胞内在的AI耐药机制包括：ER表达缺失、生长因子受体通路上调（包括ERBB受体家族、成纤维细胞生长因子受体（FGFR）、胰岛素样生长因子1受体（IGF1R））及其下游信号传导（包括MAPK和PI3K–AKT–mTOR）、细胞凋亡失调和细胞周期机制紊乱。
6. 癌细胞外在的耐药机制则依赖于与肿瘤微环境中其他细胞类型（成纤维细胞、免疫细胞、脂肪细胞和间充质干细胞）的相互作用，这些细胞共同协调了AI耐药性的形成与维持。
7. 针对细胞周期蛋白依赖性激酶4（CDK4）和CDK6、PI3K及组蛋白去乙酰化酶的机制性抑制剂，是在III期临床试验中验证的克服AI耐药性的最具前景的策略。
8. 对AI耐药机制认识的进一步深化，有赖于在多个疾病时间点采集肿瘤样本的前瞻性纵向研究，以及能全面捕捉AI耐药机制谱系及生物学的临床前模型。

英文摘要：

Oestrogen receptor-positive (ER+) breast cancer is a major cause of cancer death in women. Although aromatase inhibitors suppress the function of ER and reduce the risk of recurrence, therapeutic resistance is common and essentially inevitable in advanced disease. This Review considers both genomic and cell biological explanations as to why ER+ breast cancer cells persist, progress and cause an incurable, lethal, systemic disease. The design and outcomes of clinical trials are considered with the perspective that resistance mechanisms are heterogeneous, and therefore biomarker and somatic mutation-based stratification and eligibility will be essential for improvements in patient outcomes.

摘要翻译： 

雌激素受体阳性（ER+）乳腺癌是女性癌症死亡的主要原因。尽管芳香化酶抑制剂可抑制ER功能并降低复发风险，但治疗耐药性很常见，且在晚期疾病中几乎不可避免。本综述从基因组和细胞生物学角度探讨ER+乳腺癌细胞为何能持续存在、进展并导致无法治愈的致命性系统性疾病。文章还结合临床试验的设计与结果，指出耐药机制具有异质性，因此基于生物标志物和体细胞突变的分层与入组将是改善患者结局的关键。

原文链接：

Mechanisms of aromatase inhibitor resistance