ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2023
Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.
Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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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.
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Who cites it
16 citing papers in PubMed, 19 citations in OpenAlex.
- Milademetan in Advanced Solid Tumors with MDM2 Amplification and Wild-type TP53: Preclinical and Phase II Clinical Trial Results.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Envonalkib Versus Crizotinib in Treatment-NaiveMedComm · 2026Article
- p53 Drives Lung Cancer Regression through a TSC2/TFEB-dependent Senescence Program.Cancer discovery · 2026Article
- ZC3H15 regulates the ubiquitination of PTEN via recruitment of TRIM56 and promotes malignant progression of non-small cell lung cancer.Cell death & disease · 2026Article
- EOAI3402143 inhibits lung adenocarcinoma progression through the NF-κB/NR4A1 pathway.Acta biochimica et biophysica Sinica · 2025Article
- Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases.Annals of oncology : official journal of the European Society for Medical Oncology · 2025Article
- ZNF146 accelerates lung adenocarcinoma progression through MDM2/p53 and PHGDH/ferroptosis.Cell & bioscience · 2025Article
- The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels.Nucleic acids research · 2025Article
- Review
- Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression.Journal for immunotherapy of cancer · 2025Article
- Fatty acid metabolism-derived prognostic model for lung adenocarcinoma: unraveling the link to survival and immune response.Frontiers in immunology · 2025Article
- MDM2 drives resistance to Osimertinib by contextually disrupting FBW7-mediated destruction of MCL-1 protein in EGFR mutant NSCLC.Journal of experimental & clinical cancer research : CR · 2024Article
- Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers andJCO precision oncology · 2024Article
- Advances of E3 ligases in lung cancer.Biochemistry and biophysics reports · 2024Review
- Targeting MEK in non-small cell lung cancer.Current problems in cancer · 2024Review
- TIPE3 in Cancer: A Multifaceted Regulator of Tumorigenesis, Therapeutic Resistance, and Clinical Outcomes.Technology in cancer research & treatmentReview
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Authors and funding
19 authors at 2 institutions in 2 countries.
Funding
Abstract
introductionAlthough targeted therapies have revolutionized the therapeutic landscape of lung adenocarcinomas (LUADs), disease progression on single-agent targeted therapy against known oncogenic drivers is common, and therapeutic options after disease progression are limited. In patients with MDM2 amplification (MDM2amp) and a concurrent oncogenic driver alteration, we hypothesized that targeting of the tumor-suppressor pathway (by means of restoration of p53 using MDM2 inhibition) and simultaneous targeting of co-occurring MAPK oncogenic pathway might represent a more durably effective therapeutic strategy.
methodsWe evaluated genomic next-generation sequencing data using the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets platform to nominate potential targets for combination therapy in LUAD. We investigated the small molecule MDM2 inhibitor milademetan in cell lines and patient-derived xenografts of LUAD with a known driver alteration and MDM2amp.
resultsOf 10,587 patient samples from 7121 patients with LUAD profiled by next-generation sequencing, 6% (410 of 7121) harbored MDM2amp. MDM2amp was significantly enriched among tumors with driver alterations in METex14 (36%, p < 0.001), EGFR (8%, p < 0.001), RET (12%, p < 0.01), and ALK (10%, p < 0.01). The combination of milademetan and the MEK inhibitor trametinib was synergistic in growth inhibition of ECLC5-GLx (TRIM33-RET/MDM2amp), LUAD12c (METex14/KRAS
conclusionsCombined MDM2/MEK inhibition was found to have efficacy across multiple patient-derived LUAD models harboring MDM2amp and concurrent oncogenic drivers. This combination, potentially applicable to LUADs with a wide variety of oncogenic driver mutations and kinase fusions activating the MAPK pathway, has evident clinical implications and will be investigated as part of a planned phase 1/2 clinical trial.
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