2. Academic Validation
  3. CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells

CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells

  • Cancer Metab. 2025 Feb 7;13(1):6. doi: 10.1186/s40170-025-00375-5.
You-Yu Liu # 1 2,  Wei-Lun Huang # 2 3,  Sin-Tian Wang 3,  Hui-Ping Hsu 4,  Tzu-Ching Kao 3,  Wei-Pang Chung 5 6,  Kung-Chia Young 7 8
Affiliations

Affiliations

  • 1 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
  • 2 Center of Applied Nanomedicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
  • 3 Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, No. 1 University Rd, Tainan, 70101, Taiwan.
  • 4 Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 70101, Taiwan.
  • 5 Center of Applied Nanomedicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. edgarbun@gmail.com.
  • 6 Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, No. 1 University Rd, Tainan, 70101, Taiwan. edgarbun@gmail.com.
  • 7 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. t7908077@mail.ncku.edu.tw.
  • 8 Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, No. 1 University Rd, Tainan, 70101, Taiwan. t7908077@mail.ncku.edu.tw.
  • # Contributed equally.
PMID: 39920872 DOI: 10.1186/s40170-025-00375-5
Abstract

Background: HER2-positive patients comprise approximately 20% of breast Cancer cases, with HER2-targeted therapy significantly improving progression-free and overall survival. However, subsequent reprogramed tumor progression due to PI3K signaling pathway activation by PIK3CA mutations and/or PTEN-loss cause anti-HER2 resistance. Previously, alpha isoform-specific PI3K inhibitors were shown to potentiate HER2-targeted therapy in breast Cancer cells carrying PI3K pathway alterations with less potent effects on PTEN-loss than PIK3CA-mutant cells. Therefore, seeking for alternative combination therapy needs urgent attentions in PTEN-loss anti-HER2 resistant breast Cancer.

Methods: Since remodeling of fatty acid (FA) metabolism might contribute to HER-positive breast Cancer and is triggered by the PI3K signal pathway, herein, we examined the effects of the inhibition of endogenous FA conversion, SCD-1 or exogenous FA transport, CD36, in combination with PI3K inhibitors (alpelisib and inavolisib) in anti-HER2 resistant PTEN-loss breast Cancer cells.

Results: The activated HER2/PI3K/Akt/mTOR signaling pathway positively correlated with SCD-1 and CD36 expression in PTEN-loss breast Cancer cells. PI3K inhibition downregulated SCD-1, and accordingly, the addition of the SCD-1 inhibitor did not augment the antiproliferative effects of the PI3K inhibitors. CD36 was upregulated by blocking the PI3K signal pathway or limited serum supplementation, indicating that suppressing CD36 may decrease the excess transport of exogenous FA. The addition of the CD36 inhibitor synergistically enhanced the anti-proliferative effects of the PI3K inhibitors.

Conclusion: Simultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast Cancer.

Keywords

CD36 fatty acids transporter; Fatty acids metabolism; PI3K inhibitors; PTEN-loss; anti-HER2 resistant breast cancer.

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