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首页> 美国卫生研究院文献>Oncotarget >Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing
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Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing

机译：使用靶向下一代测序鉴定肝细胞癌PI3K / AKT / mTOR途径中的新治疗靶标

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Understanding genetic aberrations in cancer leads to discovery of new targets for cancer therapies. The genomic landscape of hepatocellular carcinoma (HCC) has not been fully described. Therefore, patients with refractory advanced/metastatic HCC referred for experimental therapies, who had adequate tumor tissue available, had targeted next generation sequencing (NGS) of their tumor samples using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA) and their treatment outcomes were analyzed. In total, NGS was obtained for 14 patients (median number of prior therapies, 1) with advanced/metastatic HCC. Of these 14 patients, 10 (71%) were men, 4 (29%) women, 6 (43%) had hepatitis B or C-related HCC. NGS revealed at least 1 molecular abnormality in 12 patients (range 0-8, median 2). Detected molecular aberrations led to putative activation of the PI3K/AKT/mTOR pathway (n=3 [mTOR, PIK3CA, NF1]), Wnt pathway (n=6 [CTNNA1, CTNNB1]), MAPK pathway (n=2 [MAP2K1, NRAS]), and aberrant DNA repair mechanisms, cell cycle control and apoptosis (n=18 [ATM, ATR, BAP1, CCND1, CDKN2A, CDK4, FGF3, FGF4, FGF19, MCL1, MDM2, RB1, TP53]). Of the 3 patients with molecular aberrations putatively activating the PI3K/AKT/mTOR pathway, 2 received therapies including a mTOR inhibitor and all demonstrated therapeutic benefit ranging from a partial response to minor shrinkage per RECIST (-30%, -15%; respectively). In conclusion, genomic alterations are common in advanced HCC. Refractory patients with alterations putatively activating the PI3K/AKT/mTOR pathway demonstrated early signals of clinical activity when treated with therapies targeting mTOR.
机译：了解癌症中的遗传畸变会导致发现新的癌症治疗靶标。肝细胞癌（HCC）的基因组格局尚未完全描述。因此，具有足够的可用肿瘤组织的难治性晚期/转移性肝癌患者接受了实验治疗，他们拥有足够的肿瘤组织，并使用Illumina HiSeq 2000平台（Foundation One，Foundation Medicine，MA）靶向了肿瘤样品的下一代测序（NGS）。分析治疗结果。总共有14例晚期/转移性HCC患者获得了NGS（先前治疗的中位数为1）。在这14例患者中，男性10例（71％），女性4例（29％），乙肝或丙肝相关性HCC占6例（43％）。 NGS在12例患者中发现至少1个分子异常（范围0-8，中位数2）。检测到的分子畸变导致PI3K / AKT / mTOR途径（n = 3 [mTOR，PIK3CA，NF1]），Wnt途径（n = 6 [CTNNA1，CTNNB1]），MAPK途径（n = 2 [MAP2K1， NRAS]），以及异常的DNA修复机制，细胞周期控制和凋亡（n = 18 [ATM，ATR，BAP1，CCND1，CDKN2A，CDK4，FGF3，FGF4，FGF19， MCL1 ， MDM2 ， RB1​​ ， TP53 ]）。在3名分子异常推定激活PI3K / AKT / mTOR通路的患者中，有2名接受了包括mTOR抑制剂在内的疗法，并且所有疗法均显示出部分获益至根据RECIST的轻微收缩（分别为-30％，-15％）。 。总之，基因组改变在晚期肝癌中很常见。难治性患者中有可能激活PI3K / AKT / mTOR通路的改变，在接受靶向mTOR的疗法时显示出临床活动的早期信号。

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