ArticleMolecular cancer2024
Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation.
Article in Molecular cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 15 citations in OpenAlex.
- Nanomaterial-driven spatiotemporal autophagy modulation: The dual-edged sword in precision cancer therapy.Acta pharmaceutica Sinica. B · 2026Review
- Circulating low-density neutrophils as biomarkers of resistance to first-line anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer.Translational oncology · 2026Article
- Multi-tyrosine kinase inhibitors: exploring immunomodulatory effects on various immune cell types in cancer.Cancer cell international · 2026Review
- The METTL3-IGF2BP3 axis drives osteosarcoma progression by enhancing ID1 mRNA stability.BMC musculoskeletal disorders · 2026Article
- Article
- A bibliometric analysis of resistance to PD-1/PD-L1 inhibitors.Frontiers in immunology · 2026Article
- Inhibitor of DNA binding 1 in lung cancer and the tumor microenvironment: a testable hypothesis for malignant pleural effusion formation.Frontiers in immunology · 2026Review
- ID1 in hematopoiesis and hematologic disorders: novel potentials of a classic differentiation regulator.Cellular & molecular biology letters · 2025Review
- A new prognostic model for lung adenocarcinoma according propionate metabolism related genes: a comprehensive bioinformatic study.Discover oncology · 2025Article
- TSC2-mutated perivascular epithelioid cell tumor with partial response to mTOR inhibition: a case report and literature review.Discover oncology · 2025Article
- Balancing between cuproplasia and copper-dependent cell death: molecular basis and clinical implications of ATOX1 in cancer.Journal of experimental & clinical cancer research : CR · 2025Review
- Integrative multi-omics analysis for identifying novel therapeutic targets and predicting immunotherapy efficacy in lung adenocarcinoma.Cancer drug resistance (Alhambra, Calif.) · 2025Article
- Hypoxia promotes pancreatic adenocarcinoma progression by stabilizing ID1 via TRIM21 suppression.Frontiers in oncology · 2025Article
- Multiple signaling pathways in the frontiers of lung cancer progression.Frontiers in immunology · 2025Review
- Current trends in sensitizing immune checkpoint inhibitors for cancer treatment.Molecular cancer · 2024Review
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Authors and funding
17 authors at 7 institutions in 2 countries.
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Abstract
backgroundThe identification of novel therapeutic strategies to overcome resistance to the MEK inhibitor trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a challenge. This study analyzes the effects of trametinib on Id1 protein, a key factor involved in the KRAS oncogenic pathway, and investigates the role of Id1 in the acquired resistance to trametinib as well as the synergistic anticancer effect of trametinib combined with immunotherapy in KRAS-mutant LUAD.
methodsWe evaluated the effects of trametinib on KRAS-mutant LUAD by Western blot, RNA-seq and different syngeneic mouse models. Genetic modulation of Id1 expression was performed in KRAS-mutant LUAD cells by lentiviral or retroviral transductions of specific vectors. Cell viability was assessed by cell proliferation and colony formation assays. PD-L1 expression and apoptosis were measured by flow cytometry. The anti-tumor efficacy of the combined treatment with trametinib and PD-1 blockade was investigated in KRAS-mutant LUAD mouse models, and the effects on the tumor immune infiltrate were analyzed by flow cytometry and immunohistochemistry.
resultsWe found that trametinib activates the proteasome-ubiquitin system to downregulate Id1 in KRAS-mutant LUAD tumors. Moreover, we found that Id1 plays a major role in the acquired resistance to trametinib treatment in KRAS-mutant LUAD cells. Using two preclinical syngeneic KRAS-mutant LUAD mouse models, we found that trametinib synergizes with PD-1/PD-L1 blockade to hamper lung cancer progression and increase survival. This anti-tumor activity depended on trametinib-mediated Id1 reduction and was associated with a less immunosuppressive tumor microenvironment and increased PD-L1 expression on tumor cells.
conclusionsOur data demonstrate that Id1 expression is involved in the resistance to trametinib and in the synergistic effect of trametinib with anti-PD-1 therapy in KRAS-mutant LUAD tumors. These findings suggest a potential therapeutic approach for immunotherapy-refractory KRAS-mutant lung cancers.
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