IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy.
IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy.
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DOI：
10.1158/1535-7163.mct-12-1067
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发表时间：
2013-07
影响因子：
5.7
通讯作者：
Deutsch E
中科院分区：
文献类型：
--
作者：
Ferté C;Loriot Y;Clémenson C;Commo F;Gombos A;Bibault JE;Fumagalli I;Hamama S;Auger N;Lahon B;Chargari C;Calderaro J;Soria JC;Deutsch E
考虑到IGF-1 R自分泌环的重要性及其在DNA损伤修复过程中的作用，胰岛素样生长因子受体-1（IGF-1 R）抑制可能是小细胞肺癌（SCLC）的相关治疗方法。我们评估了83例小细胞肺癌标本中IGF-1 R和pAkt蛋白的表达。在体外和体内，在H69、H146和H526细胞中评价了R1507（针对IGF-1 R的单克隆抗体）单独或与顺铂或电离辐射（IR）组合的功效。创新的基因组和功能的方法进行了分析不同的处理条件下的分子行为。总共有53%和37%的人类标本分别表达IGF-1 R和pAkt。R1507在H146和H526细胞中表现出单剂活性，但在H69细胞中不表现出单剂活性。R1507与顺铂和IR在体外表现出协同作用。在H526细胞中，与顺铂-IR相比，三重组合R1507-顺铂-IR导致肿瘤生长的显著延迟。分析R1507单独在体内抗肿瘤作用的明显缺乏，我们观察到体内IGF-1 R染色强度的瞬时降低，伴随着参与增殖、血管生成和存活的多种细胞表面受体和细胞内蛋白的活化。最后，我们确定了核苷酸切除修复途径（NER）后，暴露于R1507-CDDP和R1507-IR在体外和体内介导。总之，将R1507添加到当前标准顺铂-IR双联体中在选定的SCLC模型中显示出显著的化学和放射增敏作用，并且值得在临床环境中进行研究。
Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting.