Genotype-selective combination therapies for melanoma identified by high-throughput drug screening.
Genotype-selective combination therapies for melanoma identified by high-throughput drug screening.
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DOI：
10.1158/2159-8290.cd-12-0408
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发表时间：
2013-01
期刊：
影响因子：
28.2
通讯作者：
Stern DF
中科院分区：
文献类型：
--
作者：
Held MA;Langdon CG;Platt JT;Graham-Steed T;Liu Z;Chakraborty A;Bacchiocchi A;Koo A;Haskins JW;Bosenberg MW;Stern DF
对靶向单一疗法的耐药性和部分应答是癌症治疗的主要障碍。系统的方法，以确定有效的药物组合的癌症还没有很好地建立，特别是在基因型的背景下。为了解决这个问题，我们已经测试了成对组合的一系列小分子抑制剂对早期传代黑色素瘤培养物使用组合药物筛选。结果揭示了几种抑制剂组合对具有激活RAS或BRAF突变的黑色素瘤有效，包括对维罗非尼具有内在或获得性耐药性的突变BRAF黑色素瘤。EGFR和AKT的抑制使治疗抗性BRAF突变型黑素瘤培养物对维罗非尼敏感。RAS突变的黑色素瘤相对于BRAF突变对联合治疗更耐药，但在体外和体内对他汀类药物和细胞周期蛋白依赖性激酶抑制剂的联合治疗敏感。这些结果证明了组合药物筛选用于发现克服突变型BRAF和RAS驱动的黑素瘤的抗性表型的独特治疗方案的效用。
Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small molecule inhibitors on early passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGFR and AKT sensitized treatment-resistant BRAF-mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results demonstrate the utility of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF and RAS driven melanomas.