ArticleBreast cancer research : BCR2015
Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers.
Article in Breast cancer research : BCR, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Effects of Autophagy Inhibition by SAR405, a Selective VPS34 Inhibitor, on Pleural Mesothelioma Cells.Thoracic cancer · 2026Article
- Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.Molecular cancer · 2024Review
- Targeting phosphoinositide signaling in cancer: relevant techniques to study lipids and novel avenues for therapeutic intervention.Frontiers in cell and developmental biology · 2023Article
- Review
- Review
- Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics.ACS pharmacology & translational science · 2021Review
- Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma.Cancers · 2021Review
- The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer.International journal of molecular sciences · 2021Review
- Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells.International journal of molecular sciences · 2021Review
- Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma.Frontiers in pharmacology · 2021Review
- Effect of early-stage autophagy inhibition in BRAFCell death & disease · 2019Article
- Autophagy in Cancer: Regulation by Small Molecules.Trends in pharmacological sciences · 2018Review
- Novel treatment strategies for patients with HER2-positive breast cancer who do not benefit from current targeted therapy drugs.Experimental and therapeutic medicine · 2018Review
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3 authors at 1 institution in 1 country.
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Abstract
introductionHuman epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25% of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear.
methodsWe utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers.
resultsTreatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110α, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110α and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110α and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing.
conclusionsThese studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing.
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