ArticleCell communication and signaling : CCS2022
Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo.
Article in Cell communication and signaling : CCS, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- Preclinical studies of the falnidamol as a highly potent and specific active ABCB1 transporter inhibitor.BMC cancer · 2025Article
- Roles of nucleotide metabolism in pancreatic cancer.Frontiers in immunology · 2025Review
- SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition.Science advances · 2024Article
- The Role of ABCB1, ABCG2, and SLC Transporters in Pharmacokinetic Parameters of Selected Drugs and Their Involvement in Drug-Drug Interactions.Membranes · 2024Review
- BI-2865, a pan-KRAS inhibitor, reverses the P-glycoprotein induced multidrug resistance in vitro and in vivo.Cell communication and signaling : CCS · 2024Article
- Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1.Biomolecules · 2024Article
- HSF1 at the crossroads of chemoresistance: from current insights to future horizons in cell death mechanisms.Frontiers in cell and developmental biology · 2024Review
- An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer.Future oncology (London, England) · 2024Review
- Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters.Nature reviews. Cancer · 2023Review
- Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1).International journal of molecular sciences · 2023Article
- Adagrasib: First Approval.Drugs · 2023Review
- Fatty acid binding protein 5 regulates docetaxel sensitivity in taxane-resistant prostate cancer cells.PloS one · 2023Article
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMultidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849.
methodsThe cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [
resultsMRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [
conclusionsIn summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR. Video Abstract.
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