Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
Department of Oncology, Institute of Clinical Research, Odense University Hospital, 5000 Odense, Denmark.
Int J Mol Sci. 2023 Feb 24;24(5):4522. doi: 10.3390/ijms24054522.
The frequent activation of the PI3K/AKT/mTOR pathway and its crucial role in estrogen receptor-positive (ER+) breast cancer tumorigenesis and drug resistance has made it a highly attractive therapeutic target in this breast cancer subtype. Consequently, the number of new inhibitors in clinical development targeting this pathway has drastically increased. Among these, the isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Nevertheless, the clinical development of multiple inhibitors of the PI3K/AKT/mTOR pathway, in parallel with the incorporation of CDK4/6 inhibitors into the standard of care treatment in ER+ advanced breast cancer, has led to a multitude of available therapeutic agents and many possible combined strategies which complicate personalizing treatment. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer.
PI3K/AKT/mTOR 通路的频繁激活及其在雌激素受体阳性（ER+）乳腺癌发生和耐药中的关键作用，使其成为该乳腺癌亚型极具吸引力的治疗靶点。因此，针对该通路的新抑制剂在临床开发中的数量急剧增加。其中，PI3K/AKT/mTOR 通路的异构体特异性抑制剂 alpelisib 和泛 AKT 抑制剂 capivasertib 最近被批准与雌激素受体降解剂 fulvestrant 联合用于治疗在芳香酶抑制剂进展后的 ER+晚期乳腺癌。然而，PI3K/AKT/mTOR 通路的多种抑制剂的临床开发，以及 CDK4/6 抑制剂被纳入 ER+晚期乳腺癌的标准治疗中，导致了大量可用的治疗药物和许多可能的联合策略，使治疗个体化变得复杂。在这里，我们回顾了 PI3K/AKT/mTOR 通路在 ER+晚期乳腺癌中的作用，强调了该通路的各种抑制剂可能具有优越活性的基因组背景。我们还讨论了针对 PI3K/AKT/mTOR 及相关通路的药物的选定试验，以及支持针对 ER、CDK4/6 和 PI3K/AKT/mTOR 的三组合疗法在 ER+晚期乳腺癌中的临床开发的基本原理。
