Cancer Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
Mol Cancer Ther. 2012 Mar;11(3):720-9. doi: 10.1158/1535-7163.MCT-11-0505. Epub 2011 Dec 14.
The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.
MEK1 和 MEK2 抑制剂 GSK1120212 目前处于 II/III 期临床开发阶段。为了确定预测性生物标志物，对 218 种实体瘤细胞系和 81 种血液恶性肿瘤细胞系进行了 GSK1120212 的敏感性分析。对于实体瘤，RAF/RAS 突变是敏感性的强烈预测因子。在 RAF/RAS 突变系中，同时存在的 PIK3CA/PTEN 突变导致结肠癌细胞产生细胞增殖而非细胞毒性反应，因为这些细胞系中存在最大比例的共突变。在 KRAS 突变细胞系中，转录组学分析显示，表达模式提示上皮-间充质转化的细胞系对 GSK1120212 的敏感性较低。此外，某些组织类型的细胞系比例似乎也对 GSK1120212 敏感，而这些组织类型并不常见 RAF/RAS 突变。其中包括乳腺癌细胞系，三阴性乳腺癌细胞系比其他乳腺癌亚型的细胞系更敏感。我们鉴定了一个单一基因 DUSP6，其表达与 GSK1120212 的敏感性相关，而与 RAF/RAS 状态无关的表达缺失与耐药性相关。在血液肿瘤细胞系中，急性髓系白血病和慢性髓系白血病细胞系特别敏感。总的来说，这种全面的预测性生物标志物分析为 RAF/RAS 突变型实体瘤中的 GSK1120212 确定了额外的疗效生物标志物，并将 GSK1120212 的适应证扩展到了尽管肿瘤为 RAF/RAS 野生型但仍能从该治疗中获益的患者。
