Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity.
Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity.
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DOI：
10.1158/1078-0432.ccr-12-0827
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发表时间：
2012-12-01
期刊：
影响因子：
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通讯作者：
Eshleman JR
中科院分区：
文献类型：
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作者：
Cui Y;Brosnan JA;Blackford AL;Sur S;Hruban RH;Kinzler KW;Vogelstein B;Maitra A;Diaz LA Jr;Iacobuzio-Donahue CA;Eshleman JR
胰腺癌(PC)是西方世界第四大癌症死因。大多数患者患有晚期不能切除的疾病，对大多数化疗药物反应很差。PC的化疗可以通过调整其个体基因图谱来改进。我们试图确定对大类抗癌药物化疗敏感性的遗传预测因素。使用一组基因定义的人类PC细胞系，我们测试了吉西他滨(抗代谢产物)、多西他赛(抗微管)、丝裂霉素C(烷基化)、伊立替康(拓扑异构酶I抑制剂)、顺铂(交联)、KU0058948(PARP1抑制剂)、雷公藤内酯(萜类药物)和青蒿素(对照)。PC细胞对雷公藤甲素和多西紫杉醇均敏感。大多数PC细胞对吉西他滨和丝裂霉素敏感。绝大多数PC细胞对顺铂、伊立替康和PARP1抑制剂不敏感。然而，个别细胞系往往以独特的方式对这些化合物敏感。我们发现DPC4/Smad4失活使PC细胞对顺铂和伊立替康的敏感性增加2-4倍，但对吉西他滨的敏感性略低。PC细胞对雷公藤甲素均敏感，18%对PARP1抑制剂敏感。P16/CDKN2A失活的PC细胞对吉西他滨和MMC的敏感性降低3-4倍。PC细胞对化疗药物的敏感性与某些特定的基因特征有关。这些结果支持胰腺癌基因亚群存在的假设，这些遗传背景可能使人们能够在未来个性化PC的化疗。进一步的工作将需要确认这些反应并确定它们在体内的大小。
Pancreatic cancer (PC) is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for PC might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs. Using a panel of genetically defined human PC cell lines, we tested gemcitabine (anti-metabolite), docetaxel (anti-microtubule), mitomycin C (alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug) and artemisinin (control). All PC cell lines were sensitive to triptolide and docetaxel. Most PC cells were also sensitive to gemcitabine and MMC. The vast majority of PC cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized PC cells to cisplatin and irinotecan by 2–4 fold, but they were modestly less sensitive to gemcitabine. PC cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A inactivated PC cells were 3–4 fold less sensitive to gemcitabine and MMC. Chemosensitivity of PC cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of PC in the future. Further work will need to confirm these responses and determine their magnitude in vivo.