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

Jeong-Yeon Lee; Hyeong-Seok Joo; Hee-Joo Choi; Sora Jin; Hyung-Yong Kim; Ga-Young Jeong; HeeWoon An; Mi Kyung Park; Seung Eun Lee; Wan-Seop Kim; Taekwon Son; Kyueng-Whan Min; Young-Ha Oh; Gu Kong

Disclosures

J Natl Cancer Inst. 2019;111(6):609-619. 

In This Article

Abstract and Introduction

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-18amplification 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.

Introduction

Polycomb group (PcG) proteins are crucial epigenetic regulators that consist of two multicomplexes; one is polycomb-repressive complex 2 (PRC2), which catalyzes histone H3 lysine-27 tri-methylation (H3K27me3); and the other is PRC1, which recognizes H3K27me3 and maintains gene silencing via various mechanisms, including histone H2A mono-ubiquitination on lysine-119 (H2AK119ub) and blockade of transcriptional initiation machinery.[1–3] MEL-18 and its homolog BMI-1 are core components of PRC1. Our previous studies have shown the multiple roles of MEL-18 in inhibiting breast tumor initiation and progression in a PcG-independent manner,[4–9] and clinical studies support its tumor-suppressive role in several cancers.[10–13] However, unlike BMI-1, the PcG-associated function of MEL-18 in regulating gene silencing and cancer progression is poorly understood.

Human epidermal growth factor receptor (HER/ErbB) 2 is a member of the epidermal growth factor receptor family of receptor tyrosine kinases (RTKs), which triggers multiple oncogenic signals.[14] HER2 is amplified/overexpressed in 15–25% of breast cancers that is associated with aggressive phenotypes, thus it has been regarded as a major therapeutic target for breast cancer.[15,16] Trastuzumab, a humanized monoclonal antibody against the HER2 extracellular domain, is the most common drug for HER2-positive (HER2+) breast cancer,[17] but only 30% of metastatic breast cancer patients respond to treatment with trastuzumab alone, and many patients acquire resistance to continuous treatment.[18–20] Several mechanisms of trastuzumab resistance, including target alterations, ligand production, and dimerization between ErbB receptors, downstream mutations, and bypass signaling have been identified.[20,21] However, there is still a need for complete understanding of trastuzumab resistance mechanism and providing new therapeutic strategies for HER2+ breast cancer.

Although MEL-18 is located on the HER2 amplicon, its functional role in HER2+ breast cancer remains unknown. Here we investigated the genetic alteration of MEL-18 and its potential epigenetic role in HER2+ breast cancer for overcoming trastuzumab resistance.

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