ArticleProceedings of the National Academy of Sciences of the United States of America2009
Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 186 papers, 1 of them a synthesis that pooled it.
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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
186 citing papers in PubMed, 1 synthesis or guideline pooled it, 317 citations in OpenAlex.
- Top 100 most-cited articles on apoptosis of non-small cell lung cancer over the past two decades: a bibliometrics analysis.Frontiers in immunology · 2024Pooled it
- Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium.Cancer discovery · 2021Trial
- Trial
- Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2010Trial
- Molecular insights and therapeutic implications for the tumor suppressor role of LKB1 in non-small cell lung cancer.Cancer letters · 2026Review
- From Bacteria to Breakthroughs: Design and Evaluation of Gallocin-Based Peptide for Colorectal Cancer Therapeutic.Probiotics and antimicrobial proteins · 2026Article
- Genome-wide profiling identifies the genetic dependencies of cell death following EGFR inhibition.The Journal of biological chemistry · 2026Article
- Inhibition of MCL-1 and MEK Overcomes MEK Inhibitor Resistance in Triple-Negative and Inflammatory Breast Cancers.Molecular cancer therapeutics · 2025Article
- Theoretical investigation of AKT1 mutations in breast cancer: a computational approach to structural and functional insights.Journal of computer-aided molecular design · 2025Article
- LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.Nature communications · 2025Article
- A kinome drug screen identifies multi-TKI synergies and ERBB2 signaling as a therapeutic vulnerability in MYC/TYR subgroup atypical teratoid rhabdoid tumors.Neuro-oncology · 2024Article
- Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.Cancer research · 2023Article
- Sorcin promotes migration in cancer and regulates the EGF-dependent EGFR signaling pathways.Cellular and molecular life sciences : CMLS · 2023Article
- Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Elevated Methionine Flux Drives Pyroptosis Evasion in Persister Cancer Cells.Cancer research · 2023Article
- Review
- Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1.Cancer research communications · 2022Article
- Betacellulin promotes tumor development and EGFR mutant lung cancer growth by stimulating the EGFR pathway and suppressing apoptosis.iScience · 2022Article
- Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics.Cancer discovery · 2022Review
- Hybrid Pharmacophore- and Structure-Based Virtual Screening Pipeline to Identify Novel EGFR Inhibitors That Suppress Non-Small Cell Lung Cancer Cell Growth.International journal of molecular sciences · 2022Article
126 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
Non-small cell lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Such cancers are "addicted" to EGFR, and treatment with a TKI invariably leads to down-regulation of the PI3K-AKT-mTOR and MEK-ERK signaling pathways, resulting in apoptosis. Using a dual PI3K-mTOR inhibitor, NVP-BEZ235, we evaluated whether PI3K-mTOR inhibition alone induced apoptosis in these cancers. In contrast to HER2-amplified breast cancers, we found that PI3K-mTOR inhibition did not promote substantial apoptosis in the EGFR mutant lung cancers. However, blocking both PI3K-mTOR and MEK simultaneously led to apoptosis to similar levels as the EGFR TKIs, suggesting that down-regulation of these pathways may account for much of the apoptosis promoted by EGFR inhibition. In EGFR mutant lung cancers, down-regulation of both intracellular pathways converged on the BH3 family of proteins regulating apoptosis. PI3K inhibition led to down-regulation of Mcl-1, and MEK inhibition led to up-regulation of BIM. In fact, down-regulation of Mcl-1 by siRNA was sufficient to sensitize these cancers to single-agent MEK inhibitors. Surprisingly, an AKT inhibitor did not decrease Mcl-1 levels, and when combined with MEK inhibitors, failed to induce apoptosis. Importantly, we observed that the combination of PI3K-mTOR and MEK inhibitors effectively shrunk tumors in a transgenic and xenograft model of EGFR T790M-L858R cancers. These data indicate simultaneous inhibition of PI3K-mTOR and MEK signaling is an effective strategy for treating EGFR mutant lung cancers, including those with acquired resistance to EGFR TKIs.
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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.