Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer.

BACKGROUND: HER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd). METHODS: The effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model. RESULTS: Our study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model. CONCLUSION: In summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC.

FLNa negatively regulated proliferation and metastasis in lung adenocarcinoma A549 cells via suppression of EGFR.

Filamin A (FLNa) is a ubiquitously expressed cytoplasmic protein, which composes of an N-terminal actin binding domain (ABD) followed by 24 Ig-like repeats. FLNa functions as a cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and serves as a signaling intermediate. Recent studies have identified FLNa as a scaffold protein that interacts with over 90 proteins and plays vital roles in cellular signaling transduction. Mutations or defects in human FLNa gene have been shown to cause numerous developmental defects. Moreover, aberrant expression of FLNa has been observed in many cancers, such as parathyroid tumor, cervical cancer, and breast cancer. However, its role in lung adenocarcinoma has seldom been discussed. In the present study, our in vitro and in vivo studies demonstrated that silencing FLNa expression in lung cancer cell line A549 cells promoted proliferation, migration, and invasiveness of A549 cells by enhancing the activation of epidermal growth factor receptor and ERK signaling pathway. These results shed light on novel functions of FLNa in lung cancer and uncovered novel mechanisms, these results provided possible targets for the prediction and treatment for lung adenocarcinoma.

Correlation between IGF2BP2 gene polymorphism and the risk of breast cancer in Chinese Han women.

OBJECTIVE: To investigate the correlations between the polymorphism of IGF2BP2, a diabetes predisposing gene, and breast cancer risk in Chinese female with Han nationality. METHOD: The genomic DNAs were extracted from the peripheral blood drawn from 564 female breast cancer patients and 394 healthy females of Han nationality. The polymorphism of IGF2BP2 gene rs4402960 was detected by a multiplex PCR-Ligase detection reaction (PCR-LDR) assay from genomic DNA. The correlations between genotype and breast cancer risk as well as clinicopathologic characteristics were compared. RESULTS: The differences are significant between genotype distribution of IGF2BP2 gene rs4402960 (P=0.009) and allele gene frequency from both disease and control groups. Both T gene carriers (GT+TT) (OR=1.462; 95% CI, 1.127-1.897) and T allele gene (OR=1.382; 95% CI, 1.116-1.710) significantly increase the risk of breast cancer. No considerable correlations were observed between the polymorphism of rs4402960 and the clinical pathological parameters, such as age at diagnosis, lymphatic metastasis, estrogen and progesterone receptor status, cerb-B2 receptor status, and tumor staging. CONCLUSIONS: The IGF2BP2 gene rs4402960 polymorphism increases the breast cancer risk of Chinese females with Han nationality, and is a breast cancer predisposing gene.