Gopalan Priya K, Villegas Andres Gordillo, Cao Chunxia, Pinder-Schenck Mary, Chiappori Alberto, Hou Wei, Zajac-Kaye Maria, Ivey Alison M, Kaye Frederic J
Department of Medicine, University of Florida, Gainesville, FL, USA.
Current address: Sangamo Therapeutics, Richmond, CA, USA.
Oncotarget. 2018 Dec 21;9(100):37352-37366. doi: 10.18632/oncotarget.26424.
Aberrant activation of CDK4/6 kinase is the most common somatic event in non-small cell lung cancer (NSCLC). Palbociclib is a highly specific CDK4/6 inhibitor shown to inhibit cell cycle progression and promote cellular senescence. We conducted a phase 2 clinical trial of palbociclib in 19 previously-treated patients with advanced NSCLC. Only patients with p16-null staining by immunohistochemistry and documented tumor progression were eligible. The primary endpoint was tumor response rate. Palbociclib therapy alone was well-tolerated. Of 16 evaluable patients who received > 1 month of therapy, there were no objective responses. However, 8 patients (50%) with previously progressive NSCLC had stable disease (SD) lasting a range of 4-10.5 months. Median overall survival (OS) for all cases was 5.1 months, and median overall survival for the subset of patients with SD was 16.6 months. We also performed preclinical testing of palbociclib in combination with 13 different targeted or cytotoxic chemotherapeutic agents using a cell viability assay. Only the combination of palbociclib and mTOR inhibitors resulted in synergistic growth inhibition, particularly in tumors carrying RAS mutations. Our findings warrant further clinical investigation of the combination of palbociclib and mTOR inhibitors, especially in patients carrying activated RAS mutations.
细胞周期蛋白依赖性激酶4/6（CDK4/6）激酶的异常激活是非小细胞肺癌（NSCLC）中最常见的体细胞事件。帕博西尼是一种高度特异性的CDK4/6抑制剂，已显示出可抑制细胞周期进程并促进细胞衰老。我们对19例先前接受过治疗的晚期NSCLC患者进行了帕博西尼的2期临床试验。只有免疫组化显示p16阴性染色且有记录的肿瘤进展的患者才有资格入选。主要终点是肿瘤反应率。单独使用帕博西尼治疗耐受性良好。在16例接受治疗超过1个月的可评估患者中，没有客观反应。然而，8例（50%）先前病情进展的NSCLC患者病情稳定（SD），持续时间为4 - 10.5个月。所有病例的中位总生存期（OS）为5.1个月，病情稳定患者亚组的中位总生存期为16.6个月。我们还使用细胞活力测定法对帕博西尼与13种不同的靶向或细胞毒性化疗药物联合进行了临床前测试。只有帕博西尼与mTOR抑制剂联合使用可导致协同生长抑制，特别是在携带RAS突变的肿瘤中。我们的研究结果值得对帕博西尼与mTOR抑制剂联合使用进行进一步的临床研究，尤其是在携带激活型RAS突变的患者中。
