ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha-Positive, PIK3CA-Mutant Breast Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant Persister Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Recent Insights Into Breast Cancer: Molecular Pathways, Epigenetic Regulation, and Emerging Targeted Therapies.Breast cancer : basic and clinical research · 2025Review
- Evaluation of Copanlisib in Combination with Eribulin in Triple-negative Breast Cancer Patient-derived Xenograft Models.Cancer research communications · 2024Article
- Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials.Signal transduction and targeted therapy · 2022Review
- Current Research Status of Metronomic Chemotherapy in Combination Treatment of Breast Cancer.Oncology research and treatment · 2022Review
- PI3K inhibitors are finally coming of age.Nature reviews. Drug discovery · 2021Review
- The present and future of PI3K inhibitors for cancer therapy.Nature cancer · 2021Article
- Single-cell resolved imaging reveals intra-tumor heterogeneity in glycolysis, transitions between metabolic states, and their regulatory mechanisms.Cell reports · 2021Article
- Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.Medical sciences (Basel, Switzerland) · 2020Review
- For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors.Biomolecules · 2019Review
- Daily or weekly dosing with EGFR inhibitors, gefitinib and lapatinib, and AKt inhibitor MK2206 in mammary cancer models.Oncology reports · 2018Article
- Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis.Genes & diseases · 2018Review
- Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer.Oncotarget · 2017Article
- Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy.Cancer discovery · 2016Review
- First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.Annals of oncology : official journal of the European Society for Medical Oncology · 2016Article
- PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2016Article
- Pharmacology in the Era of Targeted Therapies: The Case of PI3K Inhibitors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2016Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
purposePhosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index. EXPERIMENTAL
designAntiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured.
resultsTreatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone.
conclusionsContinuous and metronomic PI3K inhibition elicits robust anticancer effects in ER(+), PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250-60. ©2016 AACRSee related commentary by Toska and Baselga, p. 2099.
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