点击蓝字,关注我们近年来,抗体缀合药物德曲妥珠单抗已经成为治疗HER2表达乳腺癌的大杀器,不论HER2高表达、低表达还是超低表达。不过,仍有大约25%至50%的患者对此药完全无效或者继发耐药。2025年6月27日,英国《自然》旗下《自然癌症》在线发表美国梅奥(妙佑)医学中心、匹兹堡大学、NSABP基金会、哈佛大学医学院达纳法伯癌症研究所、康奈尔大学、佛罗里达大学、中国清华大学、芬兰赫尔辛基大学的研究报告,发现这些对德曲妥珠单抗耐药的HER2阳性乳腺癌能够表达比普通HER2短一截的p95HER2引起免疫逃逸,从而促进肿瘤生长并产生德曲妥珠单抗耐药,问世十多年来命运坎坷的奈拉替尼对此有效。这源于p95HER2具有促进乳腺癌细胞表达程序性死亡配体PD-L1让人体免疫细胞进入自杀程序并分泌白细胞介素IL-6等免疫抑制介质的独特能力。对于临床前模型,这可削弱德曲妥珠单抗的疗效,因为其完全疗效依赖于对细胞死亡的免疫原反应。重要的是,该研究发现奈拉替尼能够有效引导蛋白酶体降解p95HER2,从而减轻其免疫抑制作用。该研究对此概念进行验证,表明奈拉替尼±p95HER2下游介质靶向药物可以恢复人体抗肿瘤免疫力和德曲妥珠单抗的疗效。因此,该研究结果表明,p95HER2能够引起HER2阳性乳腺癌的免疫抑制程序和耐药机制,奈拉替尼可以靶向p95HER2,对于改善抗体缀合药物或者肿瘤免疫治疗药物的疗效具有潜在价值。Nat Cancer. 2025 Jun 27. IF: 28.5p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2(+) breast cancer that limits trastuzumab deruxtecan efficacy.Hu D, Lyu X, Li Z, Ekambaram P, Dongre A, Freeman T, Joy M, Atkinson JM, Brown DD, Cai Z, Carleton NM, Crentsil HE, Little J 4th, Kemp F, Klei LR, Beecher M, Sperinde J, Huang W, Joensuu H, Srinivasan A, Pogue-Geile KL, Wang Y, Feng H, Eli LD, Lalani AS, Zou J, Tseng GC, Bruno TC, Lee AV, Oesterreich S, Wolmark N, Allegra CJ, Jacobs SA, McAllister-Lucas LM, Lucas PC.Mayo Clinic, Rochester, MN, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; BlueSphere Bio, Pittsburgh, PA, USA; NSABP Foundation, Inc., Pittsburgh, PA, USA; University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Cornell University, Ithaca, NY, USA; Monogram Biosciences, Laboratory Corporation of America Holdings, South San Francisco, CA, USA; Puma Biotechnology, Los Angeles, CA, USA; University of Florida Health, Gainesville, FL, USA; Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies and immuno-oncology agents poses a major challenge in treating HER2-positive breast cancer. Here we demonstrate that p95HER2, a truncated form of HER2, drives immune evasion in HER2-positive female breast cancer, enhancing tumor growth and conferring therapy resistance. This stems from the unique ability of p95HER2 to promote cancer cell-intrinsic programmed death ligand 1 expression and secretion of immunosuppressive mediators including interleukin 6. In preclinical models, this impairs the efficacy of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate (ADC) that relies on immunogenic responses to cell death for full efficacy. Importantly, we find that neratinib potently directs proteasomal degradation of p95HER2, relieving its immunosuppressive effects, and provide proof of concept that neratinib and/or agents targeting p95HER2 downstream mediators can restore antitumor immunity and trastuzumab deruxtecan efficacy. This study reveals a p95HER2-specific therapy resistance mechanism in HER2-positive female breast cancer and highlights the potential value of targeting p95HER2 to improve outcomes with ADCs or immuno-oncology agents.PMID: 40579589DOI: 10.1038/s43018-025-00969-4(来源:SIBCS)声 明凡署名原创的文章版权属《肿瘤瞭望》所有,欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用,不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导,也不应被视为诊疗建议,如果该信息被用于资讯以外的目的,本站及作者不承担相关责任。