Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence
Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence
复制标题
DOI：
10.1073/pnas.0914356107
复制
发表时间：
2010-02-09
影响因子：
11.1
通讯作者：
Furnari, Frank
中科院分区：
文献类型：
--
作者：
Mukasa, Akitake;Wykosky, Jill;Furnari, Frank
表皮生长因子受体（EGFR）基因扩增是高级胶质瘤中最常见的遗传改变，大约50%的EGFR扩增肿瘤还含有该受体的组成型活性突变形式Delta EGFR。尽管Delta EGFR极大地促进肿瘤生长，并且因此是抗神经胶质瘤疗法的有吸引力的靶标，但是最近使用EGFR激酶抑制剂的临床经验令人失望，因为抗性是常见的并且肿瘤最终复发。有趣的是，尚未确定Delta EGFR是否是维持体内胶质瘤生长所必需的，并且，通过扩展，它是否真正代表合理的治疗靶点。在这里，我们证明，在体内沉默的可调节三角洲EGFR与强力霉素减弱胶质瘤的生长，因此，它是至关重要的维持增强致瘤性。与临床经验相似，肿瘤在停滞一段时间后最终恢复了侵袭性生长，但有趣的是，没有Delta EGFR的再表达。为了确定肿瘤如何获得这种能力，我们发现一种独特的基因KLHDC 8，在本文中称为S Delta E（Delta EGFR表达的替代物）-1，在这些肿瘤中高度表达，这些肿瘤已经逃脱了对Delta EGFR的依赖。S Delta E-1也在人类神经胶质瘤中表达，并且在Delta EGFR非依赖性“逃逸者”肿瘤中敲低其表达抑制肿瘤生长。总而言之，我们得出的结论是，Delta EGFR是胶质瘤建立和维持所需的，并且胶质瘤在体内经历选择性压力，以采用替代补偿途径来在EGFR沉默的情况下保持攻击性。此类替代途径可作为Delta EGFR信号传导的替代品，因此应被视为额外治疗的潜在靶点。
Epidermal growth factor receptor (EGFR) gene amplification is the most common genetic alteration in high-grade glioma, and approximate to 50% of EGFR-amplified tumors also harbor a constitutively active mutant form of the receptor, Delta EGFR. Although Delta EGFR greatly enhances tumor growth and is thus an attractive target for anti-glioma therapies, recent clinical experiences with EGFR kinase inhibitors have been disappointing, because resistance is common and tumors eventually recur. Interestingly, it has not been established whether Delta EGFR is required for maintenance of glioma growth in vivo, and, by extension, if it truly represents a rational therapeutic target. Here, we demonstrate that in vivo silencing of regulatable Delta EGFR with doxycycline attenuates glioma growth and, therefore, that it is crucial for maintenance of enhanced tumorigenicity. Similar to the clinical experience, tumors eventually regained aggressive growth after a period of stasis, but interestingly, without re-expression of Delta EGFR. To determine how tumors acquired this ability, we found that a unique gene, KLHDC8, herein referred to as S Delta E (Substitute for Delta EGFR Expression)-1, is highly expressed in these tumors, which have escaped dependence on Delta EGFR. S Delta E-1 is also expressed in human gliomas and knockdown of its expression in Delta EGFR-independent "escaper" tumors suppressed tumor growth. Taken together, we conclude that Delta EGFR is required for both glioma establishment and maintenance, and that gliomas undergo selective pressure in vivo to employ alternative compensatory pathways to maintain aggressiveness in the event of EGFR silencing. Such alternative pathways function as substitutes for Delta EGFR signaling and should therefore be considered as potential targets for additional therapy.