Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Nashville, TN, USA.
Front Oncol. 2012 Oct 16;2:145. doi: 10.3389/fonc.2012.00145. eCollection 2012.
Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.
针对雌激素受体 α (ER) 信号的抗雌激素治疗是 ER+乳腺癌患者的主要治疗方法。虽然许多癌症对抗雌激素治疗表现出耐药性，但大量临床和实验证据表明，磷酸肌醇 3-激酶 (PI3K) 途径的过度激活促进了抗雌激素耐药性。此外，在雌激素剥夺的情况下，持续的配体非依赖性 ER 信号可能导致对内分泌治疗的耐药性。PI3K 激活几种促进细胞周期进展和存活的蛋白质。在 ER+乳腺癌细胞中，PI3K 促进配体依赖性和非依赖性 ER 转录活性。抗雌激素耐药性乳腺癌的模型通常仍然对雌激素刺激和 PI3K 抑制敏感，这表明有必要进行临床试验，联合使用针对 PI3K 和 ER 途径的药物。在此，我们综述了 PI3K 和 ER 在抗雌激素耐药性中的作用的最新发现，以及测试靶向这两条途径的药物联合治疗的临床试验。我们还讨论了在 PI3K 抑制剂联合使用时对 ER 下调剂进行临床研究的必要性。
