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Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2021-09-14 , DOI: 10.1016/j.chembiol.2021.08.011
Ratika Kunder 1 , Michelle Velyunskiy 2 , Sara F Dunne 3 , Byoung-Kyu Cho 4 , Deepak Kanojia 5 , Lauren Begg 1 , Adrienne M Orriols 6 , Erica Fleming-Trujillo 1 , Pranathi Vadlamani 1 , Alesia Vialichka 1 , Rosemary Bolin 7 , Jessica N Perrino 7 , Diane Roth 1 , Matthew R Clutter 8 , Nicolette A Zielinski-Mozny 9 , Young Ah Goo 10 , Massimo Cristofanilli 11 , Marc L Mendillo 12 , Athanassios Vassilopoulos 13 , Dai Horiuchi 14
Affiliation  

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.



中文翻译:

协同 PIM 激酶和蛋白酶体抑制作为 MYC 过表达三阴性乳腺癌的治疗策略

三阴性乳腺癌 (TNBC) 是临床结果最差的乳腺癌亚型。PIM 激酶家族已成为一种在 TNBC 中过度表达并与不良预后相关的因素。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,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。当 PIM 抑制剂与蛋白酶体抑制剂联合使用时,会产生显着的抗肿瘤作用,包括多聚泛素化蛋白的异常积累、蛋白毒性应激增加以及 NRF1 无法抵抗蛋白酶体活性的丧失。因此,

更新日期:2021-09-14
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