Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer.
Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer.
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DOI：
10.1021/acschembio.5b00368
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发表时间：
2015-12-18
影响因子：
4
通讯作者：
Rix U
中科院分区：
文献类型：
--
作者：
Sumi NJ;Kuenzi BM;Knezevic CE;Remsing Rix LL;Rix U
几种选择性CDK 4/6抑制剂正在进行非小细胞肺癌（NSCLC）的临床试验。Palbociclib（PD 0332991）被纳入肺-MAP治疗鳞状细胞肺癌（LUSQ）的II/III期试验。我们注意到palbociclib和结构相关的ribociclib（LEE 011）在LUSQ细胞中的细胞活性差异。在H157细胞和原发性肿瘤样本中应用基于无偏质谱的化学蛋白质组学方法，我们在此报告了这两种候选药物在LUSQ中不同的蛋白质组靶向特征，其中包括新型蛋白质和（仅Palbociclib）脂质激酶。除了CDK 4和6之外，我们还观察到CDK 9是两种药物的有效靶点。Palbociclib与几种不是ribociclib靶向的激酶相互作用，如调节自噬的酪蛋白激酶2和PIK 3R 4。此外，Palbociclib还与几种脂质激酶结合，最显著的是PIK 3 CD和PIP 4 K2 A/B/C。因此，我们观察到palbociclib对自噬的调节和对AKT信号传导的抑制，而不是ribociclib。
Several selective CDK4/6 inhibitors are in clinical trials for non-small cell lung cancer (NSCLC). Palbociclib (PD0332991) is included in the phase II/III Lung-MAP trial for squamous cell lung carcinoma (LUSQ). We noted differential cellular activity between palbociclib and the structurally related ribociclib (LEE011) in LUSQ cells. Applying an unbiased mass spectrometry-based chemoproteomics approach in H157 cells and primary tumor samples, we here report distinct proteome-wide target profiles of these two drug candidates in LUSQ, which encompass novel protein and, for palbociclib only, lipid kinases. In addition to CDK4 and 6, we observed CDK9 as a potent target of both drugs. Palbociclib interacted with several kinases not targeted by ribociclib, such as casein kinase 2 and PIK3R4, which regulate autophagy. Furthermore, palbociclib engaged several lipid kinases, most notably PIK3CD and PIP4K2A/B/C. Accordingly, we observed modulation of autophagy and inhibition of AKT signaling by palbociclib, but not ribociclib.