期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：6
页码：2616-2621
DOI：10.1073/pnas.0914356107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Epidermal growth factor receptor (EGFR) gene amplification is the most common genetic alteration in high-grade glioma, and {approx}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.
