Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2). In our study, two selective CRIF1–CDK2 interface inhibitors were used to investigate whether they could exert anti-proliferative activity on the TNBC cell lines. When combined with taxol treatment, these two inhibitors can advance the cells from G0/G1 to S and G2/M phases, producing irreparable damage to the cells, which then undergo apoptosis. Moreover, they enhanced the reduction in cell proliferation induced by taxol in TNBC cells, thereby improving sensitivity to taxol in these cell lines. Importantly, the inhibitors did not regulate the cell cycle in normal cells, indicating their high selectivity towards TNBC cells. Overall, the resistance to the anti-proliferative effects induced by taxol can be significantly reduced by the combined treatment with selective CRIF1–CDK2 interface inhibitors, making a conceptual advance in the CDK-related cancer treatment.

Background: The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.

Mutations. Both BRCA1 and BRCA2 genes are key players in maintaining genomic stability [1]. When mutated, cells lose the ability to repair DNA damage, leading to the accumulation of mutations and an increased risk of developing cancers, particularly those of the breast and ovaries [2]. Studies have unraveled a complex network of molecular pathways disrupted in BRCA-deficient cells, importantly cell cycle regulation and apoptotic pathways [3,4]. The BRCA1/2 mutations, though relatively rare in the general population, account for a significant proportion of breast, ovarian, and other cancers, and their implications for both patients and healthcare systems are profound [5]. The past decade has seen remarkable progress in therapies specifically targeting BRCA-mutated tumors, most notably PARP inhibitors (PARPi), although resistance remains a growing concern [6,7]. BRCA-mutated tumors also exhibit higher levels of genomic instability, generating tumor-specific neoantigens that enhance immune visibility and spurring interest in combining immune checkpoint inhibitors with DNAtargeted therapies such as PARPi. Another promising therapeutic frontier is synthetic lethality, targeting genes or pathways that, when inhibited in conjunction with BRCA mutations, lead to cancer cell death [8]. In this special issue, we bring together the latest molecular studies and therapeutic approaches to BRCA-associated cancers, shedding light on emerging insights and potential avenues for future treatments.