冷泉港实验室RaffaellaSordella博士领导的研究组称他们发现了肿瘤细胞对*有效的靶向性****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**管理局批准其上市以来，特罗凯显著地**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**某些发生了EGFR特异性致癌突变的非小细胞肺癌患者。**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**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**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**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**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**。
“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。”
原文摘要TGF-β IL-6 axis mediates selective and adaptive mechanismsof resistance to molecular targeted therapy in lung cancer
The epidermal growth-factor receptor (EGFR) tyrosine kinaseinhibitor erlotinib has been proven to be highly effective in thetreatment of nonsmall cell lung cancer (NSCLC) harboring oncogenicEGFR mutations. The majority of patients, however, will eventuallydevelop resistance and succumb to the disease. Recent studies haveidentified secondary mutations in the EGFR (EGFR T790M) andamplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG)HOS transforming gene (MET) oncogene as two principal mechanisms ofacquired resistance. Although they can account for approximately50% of acquired resistance cases together, in the remaining 50%,the mechanism remains unknown. In NSCLC-derived cell lines andearly-stage tumors before erlotinib treatment, we have uncoveredthe existence of a subpopulation of cells that are intrinsicallyresistant to erlotinib and display features suggestive ofepithelial-to-mesenchymal transition (EMT). We showed thatactivation of TGF-β–mediated signaling was sufficient to inducethese phenotypes. In particular, we determined that an increasedTGF-β–dependent IL-6 secretion unleashed previously addicted lungtumor cells from their EGFR dependency. Because IL-6 and TGF-β areprominently produced during inflammatory response, we used a mousemodel system to determine whether inflammation might impairerlotinib sensitivity. Indeed, induction of inflammation not onlystimulated IL-6 secretion but was sufficient to decrease the tumorresponse to erlotinib. Our data, thus, argue that both tumorcell-autonomous mechanisms and/or activation of the tumormicroenvironment could contribute to primary and acquired erlotinibresistance, and as such, treatments based on EGFR inhibition maynot be sufficient for the effective treatment of lung-cancerpatients harboring mutant EGFR.