AKR1C mediates the acquired resistance to T-Dxd in a HER-2 positive gastric cancer line
wang, d.; huang, q.; wang, p.; tang, f.; han, y.; wang, x.; huang, j.; shi, l.; cao, w.; zhang, z.; gu, q.
Show abstract
Trastuzumab deruxtecan (T-Dxd), an anti-HER2 antibody-drug conjugate, has significantly enhanced clinical outcomes for patients as a HER2-directed therapy compared to previous standards of care. However, acquired resistance is always a concern, necessitating further investigation into the underlying resistance mechanism. In this study, we successfully established T-Dxd-resistant cell line (N87-R) by exposing HER2-positive N87 gastric cancer cells to increasing concentrations of T-Dxd, and demonstrated its resistance phenotype both in vitro and in vivo. While there were no changes in HER2 expression or T-Dxd binding in N87-R, a signature of drug metabolism genes were found upregulated, among which AKR1C played a critical role in the resistance mechanism. The resistance phenotype of N87-R cells was mitigated by both siRNA-mediated knockdown of AKR1C and pharmacological inhibition of its enzymatic activity. Our preclinical study underscores the critical role of AKR1C function in mediating T-Dxd resistance and suggests potential therapeutic innovation for combating T-Dxd resistance.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers 95%
- Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death 94%
- Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1 94%
Similar papers in this journal
Similar papers in this journal
- Biological activity of a stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor, 60c, in metastatic, triple-negative breast cancer 95%
- REDD1 is a determinant of the sensitivity of renal cell carcinoma cells to autophagy inhibition that can be therapeutically exploited by targeting PIM kinase activity 94%
- Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase 94%
Similar papers in this journal
- Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin 95%
- The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma 94%
- Histone deacetylase inhibitor induces acetyl-CoA depletion leading to lethal metabolic stress in RAS-pathway activated cells 94%
Similar papers in this journal
- siRNA-based Therapeutic Candidate Targeting PRDM2 for Inhibition of Lung Cancer Progression 94%
- Metabolic Alterations driven by PFKFB3 upregulation confer Resistance to Trastuzumab in HER2-Positive Breast Cancer. 93%
- NRF2 upregulation by CDDO-Me protects AC16 human cardiomyocytes against doxorubicin-induced toxicity. 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.