Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Massachusetts General Hospital Cancer Center, Boston, MA 02120, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Cancer Cell. 2014 Jul 14;26(1):136-49. doi: 10.1016/j.ccr.2014.05.020. Epub 2014 Jul 4.
Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients' tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.
磷酸肌醇 3-激酶 (PI3K) 通路的激活在乳腺癌中经常发生。然而，迄今为止，单一 PI3K 抑制剂的临床疗效一直不尽如人意。对多种对 PI3K 抑制剂敏感性降低的 PIK3CA 突变型癌症进行联合药物筛选发现，联合 CDK4/6-PI3K 抑制可协同降低细胞活力。实验室研究表明，敏感型癌症在单独使用 PI3K 抑制剂治疗时会抑制 RB 磷酸化，但敏感性降低的癌症则不能抑制 RB 磷酸化。同样，对 PI3K 抑制剂 BYL719 有反应的患者肿瘤显示 pRB 抑制，而无反应的肿瘤显示 pRB 持续或增加。重要的是，PI3K 和 CDK4/6 抑制剂的联合使用克服了内在和适应性耐药性，导致 PIK3CA 突变异种移植瘤的肿瘤消退。
