冷泉港实验室发现肺癌靶向性治疗耐受新机制

冷泉港实验室证实IL-6可导致抗非小细胞肺癌（NSCLC）药特罗凯的药物敏感性下降，文章在线刊载于8月16日《Proceedings of the National Academy of Sciences》杂志。

　　

   生物通报道 多年来抗肿瘤治疗研究领域最令瞩目的成果之一就是靶向性药物的开发。这一系列靶向性药物曾被证实可在一段有限的时间内高效治疗某些陷入绝境的侵袭性肿瘤患者。

    冷泉港实验室Raffaella Sordella博士领导的研究组称他们发现了肿瘤细胞对最有效的靶向性治疗药物特罗凯（盐酸厄洛替尼片）产生耐受的机制。自从2004年美国食品和药物管理局批准其上市以来，特罗凯显著地治疗了一类难治性癌症包括非小细胞性肺癌及胰腺癌患者。
 
    特罗凯是一种表皮生长因子酪氨酸激酶抑制剂。该药被证实可有效治疗某些发生了EGFR特异性致癌突变的非小细胞肺癌患者。药物分子通过结合位于细胞膜下方的EGFR酪氨酸激酶域口袋，阻断EGFR激发的一系列可导致细胞生长失控的细胞内信号。

    近来来Sordella和他的同事们一直从事NSCLC肿瘤细胞对特罗凯耐受机制的研究。他们希望找到一种不同以往的认知解释他们搜集的一半的药物耐受案例。“我们的同事已经证明EGFR发生二次突变或是c-MET基因扩增是其中50%特罗凯耐受案例的原因，我们希望找到另一半案例发生药物耐受的原因。”

    Sordella研究组、科奈尔大学威尔医学院和维也纳波尔兹曼癌症研究所的研究人员共同研究发现了另一半案例药物耐受的机制。他们发现这些NSCLC细胞本身就对特罗凯耐受。在对这些肿瘤样本进行研究时发现有其中3%样本的细胞具有科学家们所谓的EMT特征：即正常上皮细胞转化为迁移能力增强的间充质细胞。

    这一肿瘤细胞亚群可分泌较高水平的TGF-β。TGF-β是一种生长因子在细胞分化、发育及免疫系统调控中发挥重要作用。肿瘤中TGF-β上调导致IL-6分泌增加。TGF-β和IL-6分泌增高的肿瘤细胞可以不依赖EGFR信号途径耐受特罗凯的治疗。

    “因为IL-6和TGF-β通常在炎症过程中分泌活跃，这使得我们认为炎症有可能是减少肺癌细胞对特罗凯敏感的因素之一，”Sordella说。，研究组开始研究是否在肿瘤微环境中的非癌细胞调控的炎症对于特罗凯耐受产生了影响。通过小鼠模型，研究组证实了之前的猜测。

    “IL-6影响癌细胞存活的机制尚不清楚，”Sordella指出：“我们猜测它可使细胞免于细胞程序性死亡或凋亡，我们期望在进一步的研究中证实这一猜测。”

（生物通:何嫱）

原文摘要
TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer

The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β–mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β–dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.