Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS effectors RALA and RALB, which are overexpressed in BC, as tractable molecular targets in these subtypes. While analysis of the breast cancer patient sample data suggests that the RALs are associated with poor outcome in both TNBC and HER2+ BC, our in vivo and in vitro experimental findings revealed the RALs to be essential in only the TNBC cell lines. While testing the response of the BC cell lines to the RAL inhibitors RBC8 and BQU57, we observed no correlation between drug efficacy and cell line dependency on RAL expression for survival, suggesting that these compounds kill via off-target effects. Finally, we report the discovery of a new small molecule inhibitor, OSURALi, which exhibits strong RAL binding, effectively inhibits RAL activation, and is significantly more toxic to RAL-dependent TNBC cells than RAL-independent HER2+ and normal cell lines. These results support the RALs as viable molecular targets in TNBC and the further investigation of OSURALi as a therapeutic agent.
乳腺癌是美国女性中最常见的癌症，也是癌症死亡的第二大原因。尽管RAS突变在乳腺癌中较为罕见，但三阴性乳腺癌和HER2阳性乳腺癌均表现出RAS活性增强。本研究针对这两种亚型，探讨了在乳腺癌中过度表达的RAS效应因子RALA和RALB作为可行分子靶点的潜力。对乳腺癌患者样本数据的分析表明，RALs与三阴性乳腺癌和HER2阳性乳腺癌的不良预后相关，但体内外实验结果显示RALs仅在三阴性乳腺癌细胞系中具有关键作用。在测试乳腺癌细胞系对RAL抑制剂RBC8和BQU57的反应时，我们发现药物疗效与细胞系生存对RAL表达的依赖性之间并无关联，提示这些化合物通过脱靶效应发挥作用。最后，我们报道了一种新型小分子抑制剂OSURALi的发现，该化合物与RAL结合力强，能有效抑制RAL活化，且对RAL依赖性三阴性乳腺癌细胞的毒性显著高于RAL非依赖性HER2阳性细胞系及正常细胞系。这些结果支持RALs作为三阴性乳腺癌的可行分子靶点，并为进一步研究OSURALi作为治疗药物提供了依据。
The RAL Small G Proteins Are Clinically Relevant Targets in Triple Negative Breast Cancer
肿瘤(癌症)患者之家