The amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis and HER2 gene is overexpressed in approximately 15–30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. In recent years, new targets and regimens have emerged continuously. This review discusses the fundamental mechanisms of drug resistance in the targeted therapies of HER2-positive breast cancer and summarizes recent research progress in this field, including preclinical and basic research studies.

Immune cell infiltration in liver hepatocellular carcinoma (LIHC) is promising for immunotherapy. However, effective predictive markers to accurately predict a tumour’s immune status are lacking. PSMD13, a native component of the 26 S proteasome subunit involved in intracellular metabolism, has an unclear association with cancer and immunity. Using bioinformatics analysis of data from the TCGA, we investigated the expression patterns, prognostic values, gene functions, and tumour immune relationships of PSMD13 in LIHC. We developed a prognostic model that incorporates PSMD13 for LIHC and validated the biological functions of PSMD13 in LIHC cells. Furthermore, we analysed the associations between PSMD13 expression and the tumour immune markers CD206 and CD8 in 101 paired liver tissues using immunohistochemistry. PSMD13 was upregulated in LIHC and served as a prognostic biomarker of LIHC. The knockdown of PMSD13 significantly affected the proliferation, migration, and colony formation of LIHC cells. PSMD13 was closely associated with the infiltration of M2 macrophages and the expression of various tumour immune checkpoints. Our study revealed that PSMD13 is a crucial component contributing to the malignant behaviour of LIHC, indicating its essential role in both the prognosis and potential immune microenvironment profile of LIHC.

Fenofibrate is known as a lipid-lowering drug. Although previous studies have reported that fenofibrate exhibits potential antitumor activities, IC₅₀ values of fenofibrate could be as high as 200 μM. Therefore, we investigated the antitumor activities of six synthesized fenofibrate derivatives. We discovered that one compound, SIOC-XJC-SF02, showed significant antiproliferative activity on human hepatocellular carcinoma (HCC) HCCLM3 cells and HepG2 cells (the IC₅₀ values were 4.011 μM and 10.908 μM, respectively). We also found this compound could inhibit the migration of human HCC cells. Transmission electron microscope and flow cytometry assays demonstrated that this compound could induce apoptosis of human HCC cells. The potential binding sites of this compound acting on human HCC cells were identified by mass spectrometry-cellular thermal shift assay (MS-CETSA). Molecular docking, Western blot, and enzyme activity assay-validated binding sites in human HCC cells. The results showed that fumarate hydratase may be a potential binding site of this compound, exerting antitumor effects. A xenograft model in nude mice demonstrated the anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the antitumor effect of this compound may act via activating fumarate hydratase, and this compound may be a promising antitumor candidate for further investigation.