ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 70 citations in OpenAlex.
- Inhibition of mTOR Signaling and Clinical Activity of Rapamycin in Head and Neck Cancer in a Window of Opportunity Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Trial
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- Design and biological evaluation of peptide disruptors targeting YAP1-TEAD interaction for oral cancer.BMC oral health · 2025Article
- Dual CDK and MEK Inhibition potentiates CD8Journal of experimental & clinical cancer research : CR · 2025Article
- Targeting protein synthesis pathways in MYC-amplified medulloblastoma.Discover oncology · 2025Review
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- The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma.Biomedicines · 2024Review
- Identifying drug candidates for pancreatic ductal adenocarcinoma based on integrative multiomics analysis.Journal of gastrointestinal oncology · 2024Article
- Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma.Frontiers in oncology · 2024Article
- The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches.Current molecular medicine · 2024Review
- Targeted therapy for head and neck cancer: signaling pathways and clinical studies.Signal transduction and targeted therapy · 2023Review
- Recent advances and limitations of mTOR inhibitors in the treatment of cancer.Cancer cell international · 2022Review
- Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.Neuro-oncology · 2022Article
- Precision drugging of the MAPK pathway in head and neck cancer.NPJ genomic medicine · 2022Review
- Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature.Frontiers in genetics · 2022Article
- Functionalized Nanoparticles Targeting Tumor-Associated Macrophages as Cancer Therapy.Pharmaceutics · 2021Review
- Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines.Journal of cancer research and clinical oncology · 2021Article
- Emerging RAS-directed therapies for cancer.Cancer drug resistance (Alhambra, Calif.) · 2021Review
- Dacomitinib and gedatolisib in combination with fractionated radiation in head and neck cancer.Clinical and translational radiation oncology · 2021Article
- Differential mutation spectrum and immune landscape in African Americans versus Whites: A possible determinant to health disparity in head and neck cancer.Cancer letters · 2020Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
purposeHead and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined. EXPERIMENTAL
designWe determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901).
resultsPF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo.
conclusionsPI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo.
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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.