ArticleCancer discovery2014
Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.
Article in Cancer discovery, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
121 citing papers in PubMed, 197 citations in OpenAlex.
- Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer.European journal of cancer (Oxford, England : 1990) · 2017Trial
- Oncogenic RAS as an adaptive signaling ecosystem: context-dependent vulnerabilities and resistance-informed therapeutic design.Experimental hematology & oncology · 2026Review
- From Bacteria to Breakthroughs: Design and Evaluation of Gallocin-Based Peptide for Colorectal Cancer Therapeutic.Probiotics and antimicrobial proteins · 2026Article
- PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.Cancer research · 2026Article
- The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth.Cancer gene therapy · 2026Article
- The antitumor promise of furo[2,3-RSC advances · 2026Review
- Experimentally calibrated multiscale model predicts schedule dependent drug combination effects.NPJ systems biology and applications · 2026Article
- KRAS Codon-Specific Mutations Differentially Toggle PI3K Pathway Signaling and Alter Sensitivity to Inavolisib (GDC-0077).Molecular cancer therapeutics · 2025Article
- Piperazine-Substituted Pyranopyridines Exhibit Antiproliferative Activity and Act as Inhibitors of HBV Virion Production.International journal of molecular sciences · 2025Article
- Unlocking the power of probiotics, postbiotics: targeting apoptosis for the treatment and prevention of digestive diseases.Frontiers in nutrition · 2025Review
- A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.Nature cancer · 2024Article
- Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis.Oncogene · 2024Article
- Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.World journal of oncology · 2024Review
- TRPA1 Contributes to FGFR2c Signaling and to Its Oncogenic Outcomes in Pancreatic Ductal Adenocarcinoma-Derived Cell Lines.Cancers · 2024Article
- Copanlisib population pharmacokinetics from phase I-III studies and exposure-response relationships in combination with rituximab.CPT: pharmacometrics & systems pharmacology · 2023Article
- Anticancer potential of Bacillus coagulans MZY531 on mouse H22 hepatocellular carcinoma cells via anti-proliferation and apoptosis induction.BMC complementary medicine and therapies · 2023Article
- β-Sitosterol as a Promising Anticancer Agent for Chemoprevention and Chemotherapy: Mechanisms of Action and Future Prospects.Advances in nutrition (Bethesda, Md.) · 2023Review
- Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.Bioengineering & translational medicine · 2023Article
- Therapeutic Targeting of Regulated Signaling Pathways of Non-Small Cell Lung Carcinoma.ACS omega · 2023Review
- Model-informed approach to support pediatric dosing for the pan-PI3K inhibitor copanlisib in children and adolescents with relapsed/refractory solid tumors.Clinical and translational science · 2023Article
61 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF-MEK-ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2(+) cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.