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

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Title: CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells
Authors: You-Yu Liu, Wei-Lun Huang, Sin-Tian Wang, Hui-Ping Hsu, Tzu-Ching Kao, Wei-Pang Chung, Kung-Chia Young
Source: Cancer & Metabolism, Vol 13, Iss 1, Pp 1-12 (2025)
Publisher Information: BMC, 2025.
Publication Year: 2025
Collection: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Subject Terms: anti-HER2 resistant breast cancer, PI3K inhibitors, PTEN-loss, CD36 fatty acids transporter, Fatty acids metabolism, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2049-3002
Relation: https://doaj.org/toc/2049-3002
DOI: 10.1186/s40170-025-00375-5
Access URL: https://doaj.org/article/17795fb7162c49bb9ee41b1b6ddd33e8
Accession Number: edsdoj.17795fb7162c49bb9ee41b1b6ddd33e8
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  Data: CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells
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  Data: <searchLink fieldCode="AR" term="%22You-Yu+Liu%22">You-Yu Liu</searchLink><br /><searchLink fieldCode="AR" term="%22Wei-Lun+Huang%22">Wei-Lun Huang</searchLink><br /><searchLink fieldCode="AR" term="%22Sin-Tian+Wang%22">Sin-Tian Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Hui-Ping+Hsu%22">Hui-Ping Hsu</searchLink><br /><searchLink fieldCode="AR" term="%22Tzu-Ching+Kao%22">Tzu-Ching Kao</searchLink><br /><searchLink fieldCode="AR" term="%22Wei-Pang+Chung%22">Wei-Pang Chung</searchLink><br /><searchLink fieldCode="AR" term="%22Kung-Chia+Young%22">Kung-Chia Young</searchLink>
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  Data: Cancer & Metabolism, Vol 13, Iss 1, Pp 1-12 (2025)
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  Data: 2025
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  Data: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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  Data: <searchLink fieldCode="DE" term="%22anti-HER2+resistant+breast+cancer%22">anti-HER2 resistant breast cancer</searchLink><br /><searchLink fieldCode="DE" term="%22PI3K+inhibitors%22">PI3K inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22PTEN-loss%22">PTEN-loss</searchLink><br /><searchLink fieldCode="DE" term="%22CD36+fatty+acids+transporter%22">CD36 fatty acids transporter</searchLink><br /><searchLink fieldCode="DE" term="%22Fatty+acids+metabolism%22">Fatty acids metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Neoplasms%2E+Tumors%2E+Oncology%2E+Including+cancer+and+carcinogens%22">Neoplasms. Tumors. Oncology. Including cancer and carcinogens</searchLink><br /><searchLink fieldCode="DE" term="%22RC254-282%22">RC254-282</searchLink>
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  Label: Description
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  Data: 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.
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      – Text: English
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      – SubjectFull: anti-HER2 resistant breast cancer
        Type: general
      – SubjectFull: PI3K inhibitors
        Type: general
      – SubjectFull: PTEN-loss
        Type: general
      – SubjectFull: CD36 fatty acids transporter
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      – TitleFull: CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells
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