3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer.

Human epidermal growth factor receptor 2 (HER2) aberrations are observed in various cancers. In non-small cell lung cancer, genetic alterations activating HER2, mostly exon 20 insertion mutations, occur in approximately 2-4% of cases. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate has been approved as the first HER2-targeted drug for HER2-mutant lung cancer. However, some cases are not responsive to T-DXd and the primary resistant mechanism remains unclear. In this study, we assessed sensitivity to T-DXd in JFCR-007, a patient-derived HER2-mutant lung cancer cell line. Although JFCR-007 was sensitive to HER2 tyrosine kinase inhibitors, it showed resistance to T-DXd in attachment or spheroid conditions. Accordingly, we established a three-dimensional (3D) layered co-culture model of JFCR-007, where it exhibited a lumen-like structure and became sensitive to T-DXd. In addition, an in-house inhibitor library screening revealed that G007-LK, a tankyrase inhibitor, was effective when combined with T-DXd. G007-LK increased the cytotoxicity of topoisomerase-I inhibitor, DXd, a payload of T-DXd and SN-38. This combined effect was also observed in H2170, an HER2-amplified lung cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment.

Effects of oxidized low-density lipoprotein on leukocyte-endothelial interactions in the rat mesenteric microcirculation during pregnancy.

OBJECTIVE: The accumulation of evidence implicates oxidized lipoproteins in atherosclerosis. Treatment of endothelial cells with these lipoproteins stimulates monocyte binding and the production of chemotactic factors that contribute to inflammation and endothelial injury and dysfunction. In preeclampsia, circulating low-density lipoprotein particles, which are susceptible to oxidation, are increased. We studied leukocyte-endothelial interactions that were related to oxidized lipoproteins in pregnant rats. STUDY DESIGN: We examined oxidized low-density lipoprotein-induced leukocyte behavior and uptake of fluorescent-labeled oxidized low-density lipoprotein in rat mesenteric venules during pregnancy, with the use of intravital microscopy with a video imager. RESULTS: The administration of oxidized low-density lipoprotein significantly reduced rolling velocities of leukocytes in venules and increased the numbers of leukocytes that adhered to endothelium in both nonpregnant and pregnant rats. These interactions were attenuated in pregnancy, when uptake of labeled oxidized low-density lipoprotein into leukocytes and endothelial cells also was decreased. CONCLUSION: Pregnancy may be associated with antioxidant effects.