ArticleTargeted oncology2023
Intrinsic Resistance to Osimertinib in EGFR Mutated NSCLC Cell Lines Induced by Alteration in Cell-Cycle Regulators.
Article in Targeted oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 8 citations in OpenAlex.
- Rewiring the Molecular Interplay of CDK4/6 Inhibitors in Lung Cancer: From Cell Cycle Control to Immune Microenvironment Remodeling.International journal of molecular sciences · 2026Review
- Article
- Review
- Possibilities of Overcoming Resistance to Osimertinib in NSCLC Patients with Mutations in theCancers · 2025Review
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Design, synthesis, and antiproliferative screening of new quinoline derivatives bearing aRSC advances · 2024Article
- Targeting of drug-tolerant persister cells as an approach to counter drug resistance in non-small cell lung cancer.Lung cancer (Amsterdam, Netherlands) · 2024Review
- NRP1 overexpression potentially enhances osimertinib resistance in NSCLC via activation of the PI3K/AKT signaling pathway.American journal of cancer research · 2024Article
- The potential role of next-generation sequencing in identifyingFrontiers in oncology · 2024Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundCell-cycle regulators are mutated in approximately 40% of all cancer types and have already been linked to worse outcomes in non-small cell lung cancer adenocarcinomas treated with osimertinib. However, their exact role in osimertinib resistance has not been elucidated.
objectiveIn this study, we aimed to evaluate how the CDK4/6-Rb axis may affect the sensitivity to osimertinib.
methodsWe genetically increased the level of CCND1 (Cyclin D1) and reduced the levels of CDKN2A (p16) in two different adenocarcinoma cell lines, PC9 and HCC827. We also retrospectively evaluated the outcome of patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer depending on their level of Cyclin D1 and p16.
resultsThe modified clones showed higher proliferative capacity, modifications in cell-cycle phases, and higher migratory capacity than the parental cells. Cyclin D1-overexpressing clones were highly resistant to acute osimertinib treatment. CDKN2A knockdown conferred intrinsic resistance as well, although a longer time was required for adaption to the drug. In both cases, the resistant phenotype was epidermal growth factor receptor independent and associated with a higher level of Rb phosphorylation, which was unaffected by osimertinib treatment. Blocking the phosphorylation of Rb using abemaciclib, a CDK4/6 inhibitor, exerted an additive effect with osimertinib, increasing sensitivity to this drug and reverting the intrinsic resistant phenotype. In a group of 32 patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer, assessed for Cyclin D1 and p16 expression, we found that the p16-deleted group presented a lower overall response rate compared with the control group.
conclusionsWe conclude that perturbation in cell-cycle regulators leads to intrinsic osimertinib resistance and worse patient outcomes.
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