四川大学最新Nature Cancer论文：靶向抑制FBXL2，提高T-DXd抗癌效果

Core Viewpoint - The study highlights that targeting FBXL2 can enhance HER2 expression in HER2-negative triple-negative breast cancer (TNBC) cells, making them more susceptible to trastuzumab deruxtecan (T-DXd) treatment, suggesting a viable therapeutic strategy for HER2-IHC 0 tumors [4][5][6] Group 1 - Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate that has transformed the treatment landscape for HER2-positive solid tumors [3] - The presence of high-density HER2-negative (HER2-IHC 0) cells limits the clinical efficacy of T-DXd [3] - The research published in Nature Cancer indicates that inhibiting FBXL2 can increase HER2 expression on the cell membrane of HER2-negative TNBC cells, enhancing their sensitivity to T-DXd [4][5] Group 2 - The mechanism involves FBXL2 promoting polyubiquitination and proteasomal degradation of HER2 at the K747 site [5] - Small molecules GGTi-2418 and ketoconazole can effectively increase HER2 expression by preventing FBXL2 membrane localization [5] - The study demonstrated that using lipid nanoparticles (LNP) to encapsulate GGTi-2418 and ketoconazole in HER2-IHC 0 TNBC xenograft mouse models resulted in significant and durable tumor regression when combined with T-DXd [5] Group 3 - A concurrent article in Nature Cancer emphasizes that methods to enhance HER2 expression in breast cancer could broaden the patient population eligible for T-DXd treatment [6] - The findings from the study suggest that inhibiting FBXL2 can make HER2-negative breast cancer cells sensitive to T-DXd, leading to significant tumor regression [6]