三阴性乳腺癌(TNBC)是临床预后最差的乳腺癌亚型。激酶的PIM家族已成为在TNBC中过表达并与不良结果相关的因素。临床前数据表明MYC表达升高的TNBC对PIM抑制敏感。然而,临床观察表明,PIM抑制剂作为单一药物的疗效可能有限,这表明需要联合治疗。我们的筛选工作将PIM和20S蛋白酶体抑制确定为最具协同作用的组合。PIM抑制剂,当与蛋白酶体抑制剂联合使用时,诱导显著的抗肿瘤作用,包括聚泛素化蛋白的异常积累,增加的蛋白毒性应激,以及NRF1无法抵抗蛋白酶体活性的丧失。因此,确定的组合可以代表针对MYC过表达的TNBC的合理组合疗法,该疗法易于转化为临床研究.
Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations.