p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2+ breast cancer that limits trastuzumab deruxtecan efficacy PMID: 40579589

ADC Targets in Oncology

2026-04-10

p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2+ breast cancer that limits trastuzumab deruxtecan efficacy

Nat Cancer. 2025 Jul;6(7):1202-1222. doi: 10.1038/s43018-025-00969-4.

Dong Hu ¹ ² , Xiaoshuang Lyu ³ ⁴ , Zheqi Li ⁵ ⁶ ⁷ , Prasanna Ekambaram ⁸ ⁹ , Anushka Dongre ¹⁰ , Tanner Freeman ³ ¹¹ , Marion Joy ⁶ ¹¹ , Jennifer M Atkinson ⁵ ⁶ , Daniel D Brown ⁵ ⁶ , Zongyou Cai ³ ⁴ , Neil M Carleton ⁶ , Hannah E Crentsil ³ , John Little 4th ³ , Felicia Kemp ⁸ , Linda R Klei ⁸ , Maria Beecher ³ , Jeff Sperinde ¹² , Weidong Huang ¹² , Heikki Joensuu ¹³ , Ashok Srinivasan ¹¹ , Katherine L Pogue-Geile ¹¹ , Ying Wang ¹¹ , Huichen Feng ¹¹ , Lisa D Eli ¹⁴ , Alshad S Lalani ¹⁴ , Jian Zou ¹⁵ , George C Tseng ¹⁵ , Tullia C Bruno ⁶ ¹⁶ , Adrian V Lee ⁵ ⁶ , Steffi Oesterreich ⁵ ⁶ , Norman Wolmark ⁶ ¹¹ , Carmen J Allegra ¹⁷ , Samuel A Jacobs ¹¹ , Linda M McAllister-Lucas ¹⁸ ¹⁹ ²⁰ ²¹ , Peter C Lucas ²² ²³ ²⁴ ²⁵ ²⁶

Affiliations

1. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. [email protected].
2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
4. School of Medicine, Tsinghua University, Beijing, China.
5. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
6. UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
7. Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, USA.
8. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
9. BlueSphere Bio, Pittsburgh, PA, USA.
10. Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
11. NSABP Foundation, Inc., Pittsburgh, PA, USA.
12. Monogram Biosciences, Laboratory Corporation of America Holdings, South San Francisco, CA, USA.
13. Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
14. Puma Biotechnology, Los Angeles, CA, USA.
15. Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
16. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
17. Department of Medicine, University of Florida Health, Gainesville, FL, USA.
18. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
19. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
20. Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA. [email protected].
21. Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. [email protected].
22. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. [email protected].
23. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
24. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
25. NSABP Foundation, Inc., Pittsburgh, PA, USA. [email protected].
26. Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. [email protected].

Abstract

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.