ArticleOncotarget2016
Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 33 citations in OpenAlex.
- NOP58 modulates radiosensitivity in non-small cell lung cancer via DDX18-mediated DNA damage repair.Journal of radiation research · 2026Article
- Nitroxoline Enhances Radiosensitivity in Non-Small Cell Lung Cancer by Suppressing STAT3-AKT-MTOR Survival Signaling.International journal of molecular sciences · 2026Article
- mTOR in radiotherapy of lung cancer: Mechanisms of radiation resistance and therapeutic implications (Review).International journal of oncology · 2026Review
- Impact of RAS-MAPK Pathway Genetic Alterations on Radiotherapy Response in Metastatic Lung Adenocarcinoma.JCO precision oncology · 2025Article
- Antitumor Activity of Isalpinin fromMolecules (Basel, Switzerland) · 2025Article
- CDK4/6 inhibitors in lung cancer: current practice and future directions.European respiratory review : an official journal of the European Respiratory Society · 2024Review
- YB-1 activating cascades as potential targets in KRAS-mutated tumors.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2023Review
- The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance.International journal of molecular sciences · 2022Review
- Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance.Cancers · 2022Review
- Combining radiation with PI3K isoform-selective inhibitor administration increases radiosensitivity and suppresses tumor growth in non-small cell lung cancer.Journal of radiation research · 2022Article
- Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy.Molecules (Basel, Switzerland) · 2021Review
- Metabolism of cancer cells commonly responds to irradiation by a transient early mitochondrial shutdown.iScience · 2021Article
- KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?Cancer treatment reviews · 2020Review
- Improving the Efficacy of Tumor Radiosensitization Through Combined Molecular Targeting.Frontiers in oncology · 2020Review
- New horizons from novel therapies in malignant pleural mesothelioma.Advances in respiratory medicine · 2020Review
- Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy.Cancer biology & medicine · 2019Article
- Biological Rationale for Targeting MEK/ERK Pathways in Anti-Cancer Therapy and to Potentiate Tumour Responses to Radiation.International journal of molecular sciences · 2019Review
- Review
- Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer.Clinical and translational radiation oncology · 2018Article
- MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models.Oncotarget · 2018Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite the significant contribution of radiotherapy to non-small lung cancer (NSCLC), radioresistance still occurs. One of the major radioresistance mechanisms is the hyperactivation of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through the stimulation of DNA-PKcs. We investigated if targeting PI3K would be a potential approach for enhancing the radiosensitivity of K-RAS mutated (K-RASmut) NSCLC cell lines A549 and H460. Short-term (1-2 h) pre-treatment of cells with the PI3K inhibitor PI-103 (1 μM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK-dependent Akt. However, long-term treatment with the combination of PI-103 and MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through non-homologous end joining (NHEJ) leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts. P-Akt and P-DNA-PKcs were inhibited 30 min post-irradiation in xenografts, which were pretreated by PI-103 30 min before irradiation. However, Akt was reactivated 30 min post-irradiation in tumors, which were pre-treated for 3 h with PI-103 before irradiation. After a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation. Thus, due to MEK/ERK-dependent reactivation of Akt, targeting PI3K alone is not a suitable approach for radiosensitizing K-RASmut NSCLC cells, indicating that dual targeting of PI3K and MEK is an efficient approach to improve radiotherapy outcome.
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