Comparative Analysis of Radiosensitizers for K-RAS Mutant Rectal Cancers
Comparative Analysis of Radiosensitizers for K-RAS Mutant Rectal Cancers
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DOI：
10.1371/journal.pone.0082982
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发表时间：
2013-12-12
期刊：
影响因子：
3.7
通讯作者：
Haigis, Kevin M.
中科院分区：
文献类型：
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作者：
Kleiman, Laura B.;Krebs, Angela M.;Haigis, Kevin M.
大约40%的直肠癌携带激活的K-RAS突变，这些突变与放化疗的临床反应差有关。我们的目的是鉴定与电离辐射（IR）协同作用的小分子抑制剂（SMI）（“放射增敏剂”），其可被纳入表达突变K-RAS的局部晚期直肠癌（LARC）的当前治疗策略中。我们首先优化了一种高通量测定法，用于测量SMI和IR的单独和组合效应，其产生与金标准集落形成测定法相似的结果。使用这个筛选平台和K-RAS突变的直肠癌细胞系，我们测试了靶向不同信号通路的SMI的放射增敏活性，然后在后续实验中评估了我们的最佳命中。两种最有效的放射增敏剂是Chk 1/2抑制剂AZD 7762和PI 3 K/mTOR抑制剂BEZ 235。用于治疗LARC的化疗剂5-氟尿嘧啶（5-FU）与AZD 7762协同作用，并增强AZD 7762的放射增敏作用。这项研究是第一个比较不同的SMI联合IR治疗K-RAS突变型直肠癌的研究，我们的研究结果表明，Chk 1/2抑制剂应在新的LARC临床试验中进行评估。
Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.