A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer
A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer
复制标题
DOI：
10.1126/sciadv.aav6528
复制
发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Cagan, Ross L.
中科院分区：
文献类型：
--
作者：
Bangi, Erdem;Ang, Celina;Cagan, Ross L.
结直肠癌仍然是全世界癌症死亡率的主要来源。最初的反应通常是随后出现的耐药性，对靶向治疗反应不佳，反映了目前不可治疗的癌症驱动因素，如KRAS和整体基因组复杂性。在这里，我们报告了一种新的方法来开发一种个性化的治疗耐药转移性KRAS突变结直肠癌患者的治疗。对肿瘤基因组景观的广泛基因组分析确定了9个关键驱动因素。开发了一种改变果蝇后肠中这9个基因的直系同源物的转基因模型;使用该平台进行的基于机器人的筛选将曲美替尼加唑来膦酸盐确定为候选治疗组合。治疗患者导致显著的反应：靶病灶和非靶病灶显示出强烈的部分反应，并保持稳定11个月。通过解决疾病的基因组复杂性，这种个性化的方法可以为诸如KRAS突变型结直肠癌等难治性疾病提供替代治疗选择。
Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor's genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease's genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.