MEL-18 扩增在乳腺癌抗 HER2 治疗中的作用。

Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer.

机构信息

Department of Medicine, College of Medicine.

Department of Pathology, College of Medicine.

出版信息

J Natl Cancer Inst. 2019 Jun 1;111(6):609-619. doi: 10.1093/jnci/djy151.

DOI:10.1093/jnci/djy151

PMID:30265336

Abstract

BACKGROUND

Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer.

METHODS

The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases). MEL-18 amplification was validated by fluorescence in situ hybridization (FISH) analysis. The MEL-18 effect on trastuzumab response was confirmed by in vitro cell viability assays and an in vivo xenograft experiment (n = 7 per group). Gene expression microarray and receptor tyrosine kinase array were performed to identify the trastuzumab resistance mechanism by MEL-18 loss. All statistical tests were two-sided.

RESULTS

MEL-18 was exclusively amplified in approximately 30-50% of HER2+ breast tumors and was associated with a favorable clinical outcome (disease-free survival: P = .02 in HER2+ cases, METABRIC; P = .04 in patients receiving trastuzumab). In MEL-18-amplified HER2+ breast cancer, MEL-18 depletion induced trastuzumab resistance by increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization. MEL-18 epigenetically silenced ADAM10/17 expression in cooperation with polycomb-repressive complex (PRC) 1 and PRC2. Combination treatment with an ADAM10/17 inhibitor and trastuzumab could overcome MEL-18 loss-mediated trastuzumab resistance in vivo (BT474/shMEL-18 xenograft: trastuzumab, mean [SD] tumor volume = 406.1 [50.1] mm3, vs trastuzumab + GW280264 30 mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm3, P < .001). Consistently, trastuzumab-treated patients harboring concomitant MEL-18 amplification and low ADAM17 expression showed prolonged relapse-free survival (P = .02 in our cohort, n = 213).

CONCLUSION

MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer.

摘要

背景

曲妥珠单抗（trastuzumab）治疗 HER2 靶向耐药仍然是 HER2 扩增肿瘤的主要挑战。在这里，我们研究了多梳基因 MEL-18 作为 HER2 阳性（HER2+）乳腺癌曲妥珠单抗耐药的新型预后标志物的潜在作用。

方法

我们在多个乳腺癌队列中检查了 MEL-18 的遗传改变及其临床相关性，包括 METABRIC（n=1980）、TCGA（n=825）和我们的临床标本（n=213，曲妥珠单抗治疗的 HER2+病例）。通过荧光原位杂交（FISH）分析验证 MEL-18 扩增。通过体外细胞活力测定和体内异种移植实验（每组 n=7）证实了 MEL-18 对曲妥珠单抗反应的影响。通过基因表达微阵列和受体酪氨酸激酶阵列来鉴定由 MEL-18 缺失引起的曲妥珠单抗耐药机制。所有统计检验均为双侧检验。

结果

MEL-18 仅在约 30-50%的 HER2+乳腺癌肿瘤中扩增，与良好的临床结局相关（无病生存期：在 HER2+病例中 P=0.02，METABRIC；在接受曲妥珠单抗治疗的患者中 P=0.04）。在 MEL-18 扩增的 HER2+乳腺癌中，MEL-18 耗竭通过增加 ADAM 剪切酶介导的 ErbB 配体产生和受体异二聚化诱导曲妥珠单抗耐药。MEL-18 与多梳抑制复合物（PRC）1 和 PRC2 合作，表观遗传沉默 ADAM10/17 的表达。曲妥珠单抗联合 ADAM10/17 抑制剂可在体内克服 MEL-18 缺失介导的曲妥珠单抗耐药（BT474/shMEL-18 异种移植：曲妥珠单抗，平均[标准差]肿瘤体积=406.1[50.1]mm3，vs 曲妥珠单抗+GW280264 30mg/kg，平均[标准差]肿瘤体积=68.4[15.6]mm3，P<0.001）。一致地，在我们的队列（n=213）中，接受曲妥珠单抗治疗且同时存在 MEL-18 扩增和低 ADAM17 表达的患者表现出更长的无复发生存期（P=0.02）。