Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors.
Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors.
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DOI：
10.1158/0008-5472.can-08-4327
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Settleman J
中科院分区：
文献类型：
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作者：
McDermott U;Ames RY;Iafrate AJ;Maheswaran S;Stubbs H;Greninger P;McCutcheon K;Milano R;Tam A;Lee DY;Lucien L;Brannigan BW;Ulkus LE;Ma XJ;Erlander MG;Haber DA;Sharma SV;Settleman J
血小板衍生生长因子受体（PDGFR）及其配体在几种人类恶性肿瘤中发挥重要作用。舒尼替尼是一种临床批准的多靶点酪氨酸激酶抑制剂，可抑制VEGFR、c-KIT和PDGFR，并已证明在多种实体肿瘤中具有临床活性。在胃肠道间质瘤（gist） （PDGFRA突变）和慢性髓性白血病（BCR-PDGFRA易位）中已经描述了PDGFR信号的激活，舒尼替尼可以在这两种情况下产生临床益处。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揭示更多的患者群体可能受益于抗PDGFR治疗，如舒尼替尼。使用高通量癌细胞系筛选平台，我们发现637个测试的人类肿瘤来源细胞系中只有2个对单剂舒尼替尼暴露表现出显著的敏感性。这两种细胞系（一种非小细胞肺癌和一种横纹肌肉瘤）表达高度磷酸化的PDGFRA。在舒尼替尼敏感的腺鳞NSCLC细胞系中，PDGFRA表达与局灶性PFGRA基因扩增相关，这在一小部分鳞状细胞NSCLC原发肿瘤标本中也同样检测到。此外，在该NSCLC细胞系中，还检测到编码PDGFR配体PDGFC基因的局灶扩增，通过RNA干扰沉默PDGFRA或PDGFC表达抑制增殖。在舒尼替尼敏感横纹肌肉瘤细胞系中观察到类似的PDGFRA和PDGFC的共同依赖性。这些发现表明，除了gist外，PDGFC介导的PDGFRA激活的罕见肿瘤也可能对药理学PDGFRA或PDGFC抑制有临床反应。
Platelet-derived growth factor receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically-approved multi-targeted tyrosine kinase inhibitor which inhibits VEGFR, c-KIT, and PDGFR, and has demonstrated clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (GISTs) (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 out of 637 tested human tumor-derived cell lines demonstrate significant sensitivity to single-agent sunitinib exposure. These two cell lines (a NSCLC and a rhabdomyosarcoma) demonstrated expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adeno-squamous 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 co-dependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to GISTs, rare tumors that demonstrate PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.