Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy.
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Medical Oncology A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy.
Crit Rev Oncol Hematol. 2021 Jun;162:103334. doi: 10.1016/j.critrevonc.2021.103334. Epub 2021 Apr 15.
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.
磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/雷帕霉素靶蛋白（mTOR）信号通路在许多人类肿瘤中经常失调，包括乳腺癌。PI3Kα催化亚基（PIK3CA）的体细胞突变是通路过度激活的最常见原因。因此，已经研究了几种 PI3K 抑制剂，其中一种，阿培利司，最近被批准用于治疗内分泌敏感、PIK3CA 突变的转移性乳腺癌。不幸的是，所有接受 PI3K 抑制剂治疗的患者最终都会对这些药物产生耐药性。耐药机制包括致癌性 PI3K 改变、通过上游或下游效应物重新激活通路以及增强平行的生存途径。我们回顾了 PI3K 改变在乳腺癌中的预后和预测作用，重点关注对 PI3K 抑制剂的耐药性和具有潜在临床相关性的生物标志物。我们还讨论了可能克服 PI3K 抑制剂耐药性的联合策略，从而提高这些药物在乳腺癌中的疗效。
