Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer.
Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer.
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DOI：
10.1111/cas.13546
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发表时间：
2018-04
期刊：
影响因子：
5.7
通讯作者：
Toyooka S
中科院分区：
文献类型：
--
作者：
Yoshioka T;Shien K;Namba K;Torigoe H;Sato H;Tomida S;Yamamoto H;Asano H;Soh J;Tsukuda K;Nagasaka T;Fujiwara T;Toyooka S
分子靶向治疗在癌症治疗方面取得了显著进展。虽然已经开发了各种抗人表皮生长因子受体2（HER 2）药物，但曲妥珠单抗仍然是目前唯一可用于胃癌的抗HER 2药物。在这项研究中，我们为HER 2阳性胃癌患者提出了新的治疗选择。首先，我们确定了12种胃癌细胞系的分子特征，并检查了泛HER抑制剂阿法替尼和来那替尼在这些细胞系中的抗肿瘤作用。此外，我们分析了123例日本患者切除的原发性胃癌中的HER 2改变，以澄清可能对这些药物有反应的候选人。在药物敏感性分析中，阿法替尼和来那替尼均在大多数HER 2扩增细胞系中产生抗肿瘤作用。然而，有些细胞对药物不敏感。当基于药物敏感性比较细胞的分子谱时，我们发现IGFBP 7（一种抑制胰岛素样生长因子-1受体（IGF-1 R）活化的肿瘤抑制基因）的mRNA表达水平较低的癌细胞对泛HER抑制剂的敏感性较低。由泛HER抑制剂和IGF-1 R抑制剂苦鬼臼脂素组成的联合治疗显示出显著的协同作用。在123例临床样本中，我们发现19例HER 2扩增和3例致癌突变。总之，阿法替尼和来那替尼是治疗HER 2扩增胃癌的有前景的治疗选择。除了HER 2扩增，IGFBP 7可能是对这些药物敏感的生物标志物，IGF-1 R靶向治疗可以克服HER 2扩增胃癌的药物不敏感性。
Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti‐human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti‐HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2‐positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan‐HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2‐amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin‐like growth factor‐1 receptor (IGF‐1R), were less sensitive to pan‐HER inhibitors. A combination therapy consisting of pan‐HER inhibitors and an IGF‐1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2‐amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF‐1R‐targeting therapy can overcome drug insensitiveness in HER2‐amplified gastric cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8
作者：
Landberg, G;Östlund, H;Seth, A
通讯作者：
Seth, A
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
11.2
作者：
Shigematsu, H;Takahashi, T;Gazdar, AF
通讯作者：
Gazdar, AF
影响因子：
16.6
作者：
Pereira B;Chin SF;Rueda OM;Vollan HK;Provenzano E;Bardwell HA;Pugh M;Jones L;Russell R;Sammut SJ;Tsui DW;Liu B;Dawson SJ;Abraham J;Northen H;Peden JF;Mukherjee A;Turashvili G;Green AR;McKinney S;Oloumi A;Shah S;Rosenfeld N;Murphy L;Bentley DR;Ellis IO;Purushotham A;Pinder SE;Børresen-Dale AL;Earl HM;Pharoah PD;Ross MT;Aparicio S;Caldas C
通讯作者：
Caldas C