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JNCI-J. Natl. Cancer Inst., Published: 27 September 2018 | https://doi.org/10.1093/jnci/djy151 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, Hee Woon An, Mi Kyung Park, Seung Eun Lee, Wan-Seop Kim, Taekwon Son, Kyueng-Whan Min, Young-Ha Oh, Gu Kong

Affiliations of authors: Department of Medicine, College of Medicine (JYL) and Department of Pathology, College of Medicine (HSJ, HJC, SJ, HYK, GYJ, HWA, KWM, YHO, GK), Hanyang University, Seoul, Republic of Korea; National Cancer Center, Goyang, Republic of Korea (MKP); Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea (SEL, WSK); Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea (TS).

^*These authors contributed equally to this work.

Correspondence to: Gu Kong, MD, PhD, Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea

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 30mg/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.

논문정보

형식Research article
게재일2018년 09월 (BRIC 등록일 2018-10-02)
연구진국내 연구진
분야 의약학 > 종양의학

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