Weisberg Ellen, Wright Renee D, Jiang Jingrui, Ray Arghya, Moreno Daisy, Manley Paul W, Fabbro Doriano, Hall-Meyers Elizabeth, Catley Laurie, Podar Klaus, Kung Andrew L, Griffin James D
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Gastroenterology. 2006 Dec;131(6):1734-42. doi: 10.1053/j.gastro.2006.09.017. Epub 2006 Sep 20.
BACKGROUND & AIMS: Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib.
The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo.
PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA.
Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.
在一部分不表达突变干细胞因子受体c-kit的胃肠道间质瘤（GIST）患者中，已报道血小板衍生生长因子受体α（PDGFRA）存在激活突变。突变型PDGFRA阳性GIST对伊马替尼的反应性取决于PDGFRA突变的位置；例如，V561D近膜结构域突变比D842V激酶结构域突变对伊马替尼更敏感。在本研究中，我们比较了3种酪氨酸激酶抑制剂PKC412、尼罗替尼和伊马替尼对2种与GIST相关的PDGFRA突变体V561D和D842V的影响，这两种突变体对伊马替尼具有不同的敏感性。
通过对V561D或D842V-PDGFRA突变体进行体外增殖研究，评估PKC412、尼罗替尼和伊马替尼单独及联合使用的效果。在体内研究尼罗替尼和PKC412单独及联合使用的效果。
PKC412在体外对V561D-PDGFRA突变体以及在体外和体内对D842V-PDGFRA突变体均有强效抑制作用。伊马替尼和尼罗替尼在体外对V561D-PDGFRA突变体均显示出强效活性，但对D842V-PDGFRA的疗效明显较差。然而，当尼罗替尼与伊马替尼或PKC412联合使用时，未显示出拮抗作用，而是以协同方式作用于D842V-PDGFRA。
我们的研究结果支持对PKC412治疗突变型PDGFRA-GIST进行临床试验。数据还支持将尼罗替尼用作V561D-PDGFRA相关GIST的治疗选择，尽管D842V-PDGFRA敏感性降低可能限制尼罗替尼单药治疗D842V-PDGFRA相关GIST的潜力。
