2. Academic Validation
  3. CD24 overexpression confers resistance to Pyrotinib through inhibiting autophagy in patients with HER2-positive breast cancer

CD24 overexpression confers resistance to Pyrotinib through inhibiting autophagy in patients with HER2-positive breast cancer

  • Int J Biol Macromol. 2026 Feb:346:150649. doi: 10.1016/j.ijbiomac.2026.150649.
Yue Gao 1,  Xinglu Zhou 2,  Yi Lu 3,  Jiming Yang 4,  Bao Deng 5,  Zhangdi Yan 6,  Xichuan Li 7,  Zhenkun Fu 8,  Lei Zhong 9
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: [email protected].
  • 2 Department of PET/CT Center, Harbin Medical University Cancer Hospital, Harbin, China. Electronic address: [email protected].
  • 3 Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: [email protected].
  • 4 Department of Pharmacy, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: [email protected].
  • 5 Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: [email protected].
  • 6 Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: [email protected].
  • 7 Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, China. Electronic address: [email protected].
  • 8 Department of Immunology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China. Electronic address: [email protected].
  • 9 Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: [email protected].
PMID: 41633453 DOI: 10.1016/j.ijbiomac.2026.150649
Abstract

Human epidermal growth factor receptor 2-positive (HER2+) breast Cancer (BC) constitutes the most challenging subtype of BC, characterized by aggressive tumor proliferation, rapid metastatic potential, and a high propensity for developing resistance, which collectively contribute to a poor clinical prognosis. While the introduction of the novel HER2 inhibitor Pyrotinib has significantly improved therapeutic outcomes, its effectiveness as a monotherapy was substantially constrained by the emergence of acquired resistance. Consequently, discovering novel targeted agents to enhance Pyrotinib's therapeutic effectiveness through combination therapy was urgently required. Cluster of differentiation 24 (CD24) has been identified as a novel immune checkpoint that contributes to tumor-associated immune suppression, however, its involvement in resistance to Pyrotinib remains inadequately understood. In this study, we elucidated the role of CD24 in Pyrotinib-resistant HER2+ BC. Our results demonstrated that CD24 expression was elevated in Pyrotinib-resistant HER2+ BC cells. In vitro experiments revealed that silencing CD24 inhibited proliferation, migration, and invasion of HER2+ BC cells while promoting Autophagy, whereas overexpression of CD24 produced opposite effects. Furthermore, CD24 knockdown reduced its expression level by promoting the ubiquitination modification of epidermal growth factor receptor (EGFR), and significantly inhibited its downstream Akt/mTOR signaling pathway. By interacting with EGFR and modulating the mTOR pathway, CD24 acted as a critical regulator of autophagic cell death, thereby enhancing the sensitivity of HER2+ BC cells and reversing Pyrotinib resistance.

Keywords

CD24; HER2+ breast cancer; Pyrotinib resistance.

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