配体依赖性血小板衍生生长因子受体(PDGFR)α激活使肺癌和肉瘤细胞对PDGFR激酶抑制剂敏感。

PubMed ID
发表日期 2009年May月

原始出处 癌症研究
Cancer research
作者 McDermott  Ultan  Ames  Rachel Y  Iafrate  A John  Maheswaran  Shyamala  Stubbs  Hannah  Greninger  Patricia  McCutcheon  Kaitlin  Milano  Randy  Tam  Angela  Lee  Diana Y  Lucien  Laury  Brannigan  Brian W  Ulkus  Lindsey E  Ma  Xiao-Jun  Erlander  Mark G  Haber  Daniel A  Sharma  Sreenath V  Settleman  Jeffrey 

文献标题 配体依赖性血小板衍生生长因子受体(PDGFR)α激活使肺癌和肉瘤细胞对PDGFR激酶抑制剂敏感。
Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors.

文献摘要

血小板衍生生长因子受体(PDGFR)及其配体在多种人类恶性肿瘤中发挥着重要作用。苏尼替尼是一种临床认可的多靶点酪氨酸激酶抑制剂,可抑制血管内皮生长因子受体、c-KIT和PDGFR,并在各种实体瘤中显示出临床活性。在胃肠道间质瘤(PDGFRA突变)和慢性髓性白血病(BCR-PDGFRA易位)中,PDGFR信号的激活已经被描述,sunitinib在这两种情况下都能产生临床效益。然而,在其他肿瘤类型中发现PDGFR激活突变或基因重排,可能会发现更多的患者群体可能受益于抗PDGFR治疗,如sunitinib。利用高通量肿瘤细胞株筛选平台,我们发现637株人肿瘤细胞株中只有2株对单一药物sunitinib暴露有显著的敏感性。这两个细胞系[一个非小细胞肺癌(NSCLC)和一个横纹肌肉瘤]显示高磷酸化PDGFRA的表达。在sunitinib敏感的腺鳞状非小细胞肺癌细胞系中,PDGFRA的表达与PFGRA基因的扩增有关,在鳞状非小细胞肺癌原发肿瘤中也有类似的检测。此外,在NSCLC细胞系中,还检测到PDGFR配体PDGFC基因的局部扩增,RNA干扰抑制PDGFRA或PDGFC的表达抑制增殖。在sunitinib敏感的横纹肌肉瘤细胞系中,PDGFRA和PDGFC的相关性相似。这些发现表明,除了胃肠道间质肿瘤外,显示PDGFC介导的PDGFRA激活的罕见肿瘤也可能对药物PDGFRA或PDGFC抑制有临床反应。


Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non-small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.


获取全文 10.1158/0008-5472.CAN-08-4327