Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: Rationale for patient selection
Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: Rationale for patient selection
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DOI：
10.1158/0008-5472.can-06-3633
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Clark, Edwin
中科院分区：
文献类型：
--
作者：
Huang, Fei;Reeves, Karen;Clark, Edwin
达沙替尼是一种多靶点激酶抑制剂，最近被批准用于治疗对先前治疗耐药或不耐受的慢性粒细胞白血病和费城染色体阳性急性淋巴细胞白血病。它还处于治疗实体瘤患者的临床试验中。预测达沙替尼反应的分子标志物的鉴定可以通过选择最有可能获得临床获益的患者来协助临床开发。通过对 23 种乳腺癌细胞系进行基线基因表达谱分析，我们确定了与达沙替尼体外敏感性高度相关的基因组特征。这些特征预测达沙替尼敏感性的能力在独立的测试细胞系中得到了进一步证实和验证。使用六基因模型正确预测了 12 个乳腺癌细胞系中的 11 个 (92%) 和 23 个肺癌细胞系中的 19 个 (83%) 的达沙替尼敏感性。实时定量PCR和免疫组织化学检测进一步证实了所选标记物的差异表达模式。最后，在原发性乳腺、肺和卵巢肿瘤的子集中观察到这些基因特征，表明在患者选择中具有潜在的用途。表达达沙替尼敏感特征的乳腺癌患者亚型包括独特的临床和分子亚组：所谓的“三阴性”（即雌激素受体阴性、孕激素受体阴性和 HER2 阴性）或“基础”乳腺癌亚型。该患者群体预后较差，目前有效的治疗选择很少。我们的结果表明，达沙替尼可能是这一难治人群的一种有价值的治疗选择。为了检验这一假设，目前正在进行临床研究以确定达沙替尼在这些患者中的活性。
Dasatinib is a multitargeted kinase inhibitor that was recently approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. It is also in clinical trials for treating patients with solid tumors. The identification of molecular markers predictive of response to dasatinib could assist in clinical development by selecting patients most likely to derive clinical benefit. Using baseline gene expression profiling of a panel of 23 breast cancer cell lines, we identified genomic signatures highly correlated with in vitro sensitivity to dasatinib. The ability of these signatures to predict dasatinib sensitivity was further confirmed and validated in independent test cell lines. A six-gene model was used to correctly predict dasatinib sensitivity in 11 out of 12 (92%) additional breast and 19 out of 23 (83%) lung cancer cell lines. Quantitative real-time PCR and immunohistochemical assays further confirmed the differential expression pattern of selected markers. Finally, these gene signatures were observed in a subset of primary breast, lung, and ovarian tumors suggesting potential utility in patient selection. The subset of breast cancer patients expressing the dasatinib-sensitive signature includes a distinct clinical and molecular subgroup: the so-called "triple negative" (i.e., estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) or "basal" breast cancer subtype. This patient population has a poor prognosis and currently has few effective treatment options. Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients.