{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:06:39Z","timestamp":1761523599281},"reference-count":28,"publisher":"Proceedings of the National Academy of Sciences","issue":"34","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,8,26]]},"abstract":"<jats:p>The clinical efficacy of selective kinase inhibitors suggests that some cancer cells may become dependent on a single oncogene for survival. RNAi has been increasingly used to understand such \u201concogene addiction\u201d and validate new therapeutic targets. However, RNAi approaches suffer from significant off-target effects that limit their utility. Here, we combine carefully titrated lentiviral-mediated short hairpin RNA knockdown of the epidermal growth factor receptor (EGFR) with heterologous reconstitution by EGFR mutants to rigorously analyze the structural features and signaling activities that determine addiction to the mutationally activated EGFR in human lung cancer cells. EGFR dependence is differentially rescued by distinct EGFR variants and oncogenic mutants, is critically dependent on its heterodimerization partner ErbB-3, and surprisingly, does not require autophosphorylation sites in the cytoplasmic domain. Quantitative \u201concogene rescue\u201d analysis allows mechanistic dissection of oncogene addiction, and, when broadly applied, may provide functional validation for potential therapeutic targets identified through large-scale RNAi screens.<\/jats:p>","DOI":"10.1073\/pnas.0803217105","type":"journal-article","created":{"date-parts":[[2008,8,19]],"date-time":"2008-08-19T01:09:09Z","timestamp":1219108149000},"page":"12480-12484","update-policy":"http:\/\/dx.doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Modeling oncogene addiction using RNA interference"],"prefix":"10.1073","volume":"105","author":[{"given":"S. Michael","family":"Rothenberg","sequence":"first","affiliation":[{"name":"*Massachusetts General Hospital Cancer Center,"},{"name":"Howard Hughes Medical Institute and"},{"name":"Harvard Medical School, Charlestown, MA 02129; and"}]},{"given":"Jeffrey A.","family":"Engelman","sequence":"additional","affiliation":[{"name":"*Massachusetts General Hospital Cancer Center,"},{"name":"Harvard Medical School, Charlestown, MA 02129; and"}]},{"given":"Sheila","family":"Le","sequence":"additional","affiliation":[{"name":"*Massachusetts General Hospital Cancer Center,"}]},{"suffix":"II","given":"David J.","family":"Riese","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907"}]},{"given":"Daniel A.","family":"Haber","sequence":"additional","affiliation":[{"name":"*Massachusetts General Hospital Cancer Center,"},{"name":"Howard Hughes Medical Institute and"},{"name":"Harvard Medical School, Charlestown, MA 02129; and"}]},{"given":"Jeffrey","family":"Settleman","sequence":"additional","affiliation":[{"name":"*Massachusetts General Hospital Cancer Center,"},{"name":"Harvard Medical School, Charlestown, MA 02129; and"}]}],"member":"341","published-online":{"date-parts":[[2008,8,26]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/22788"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80367-6"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/71691"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104053441401"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040938"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099314"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405220101"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05610"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1006-777"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1173"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt831"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04791"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1258"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.01.040"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.7078"},{"key":"e_1_3_3_16_2","first-page":"4568","article-title":"A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis","volume":"7","author":"Honegger AM","year":"1987","unstructured":"AM Honegger, et al., A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol Cell Biol 7, 4568\u20134571 (1987).","journal-title":"Mol Cell Biol"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0020073"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0453"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4625"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4293"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.16.7727"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.12.7192"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409773102"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.14.6.3550-3558.1994"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0462"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.03.015"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510284103"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051918"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0803217105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T20:47:00Z","timestamp":1649796420000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0803217105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8,26]]},"references-count":28,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2008,8,26]]}},"alternative-id":["10.1073\/pnas.0803217105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0803217105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,8,26]]},"assertion":[{"value":"2008-04-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-08-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}