Targeting SRC in mucinous ovarian carcinoma.
Targeting SRC in mucinous ovarian carcinoma.
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DOI：
10.1158/1078-0432.ccr-10-3176
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发表时间：
2011-08-15
期刊：
影响因子：
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通讯作者：
Sood AK
中科院分区：
文献类型：
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作者：
Matsuo K;Nishimura M;Bottsford-Miller JN;Huang J;Komurov K;Armaiz-Pena GN;Shahzad MM;Stone RL;Roh JW;Sanguino AM;Lu C;Im DD;Rosenshien NB;Sakakibara A;Nagano T;Yamasaki M;Enomoto T;Kimura T;Ram PT;Schmeler KM;Gallick GE;Wong KK;Frumovitz M;Sood AK
与其他亚型卵巢癌相比，黏液性卵巢癌具有独特的临床模式。在这里，我们评估了(i)在一个大型队列中粘液性卵巢癌的分期特异性临床意义（ii） src激酶在粘液性卵巢癌临床前模型中的功能作用。对1302例卵巢癌患者进行生存分析，其中122例（9.4%）为粘液癌。在一种新型原位黏液性卵巢癌模型（RMUG-S-ip2）中，使用达沙替尼为基础的治疗测试了src激酶抑制的生物学效应。晚期黏液性卵巢癌患者的生存期明显低于浆液性组织学患者：中位总生存期为1.67年对3.41年，p=0.002；复发后中位生存时间分别为0.53年和1.66年，p<0.0001。在多种卵巢癌细胞系中，RMUG-S-ip2粘液性卵巢癌细胞的src激酶活性最高。此外，奥沙利铂治疗诱导src激酶磷酸化。奥沙利铂治疗诱导的这种活性被同时给予达沙替尼抑制。在体内用达沙替尼靶向src在RMUG-S-ip2模型中显示出显著的抗肿瘤作用，而在浆液性卵巢癌（SKOV3-TR）模型中则没有。在RMUG-S-ip2模型中，奥沙利铂联合达沙替尼进一步显示出降低细胞活力、增加细胞凋亡和体内抗肿瘤作用的显著作用。我们的研究结果表明，患有黏液性卵巢癌的女性生存率低与细胞毒性治疗的耐药性有关。靶向src激酶联合达沙替尼和奥沙利铂可能是一种有吸引力的方法。
Mucinous ovarian carcinomas have a distinct clinical pattern compared to other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of src kinase in pre-clinical models of mucinous ovarian carcinoma. 1302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of src kinase inhibition were tested in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2) using dasatinib-based therapy. Patients with advanced-stage mucinous ovarian cancer had significantly worse survival compared to those with serous histology: median overall survival, 1.67 versus 3.41 years, p=0.002; and median survival time after recurrence of 0.53 versus 1.66 years, p<0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting src with dasatinib in vivo showed significant anti-tumor effects in the RMUG-S-ip2 model, but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further demonstrated significant effects on reducing cell viability, increasing apoptosis, and in vivo anti-tumor effects in the RMUG-S-ip2 model. Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting src kinase with combination of dasatinib and oxaliplatin may be an attractive approach in this disease.