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The antibody has limited skin toxicity and is generally well tolerated. Similar to other anti\u2010<jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content> therapies, patients may relapse a few months after treatment. In this study we show for the first time, the use of <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>imotuzumab along with <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>irolimus has synergistic effect on tumor inhibition as compared with the drugs used individually, in <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>imotuzumab responsive and nonresponsive cell lines. In vitro studies prove that while <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>irolimus (25\u00a0nmol\/L) affects the signal downstream to <jats:styled-content style=\"fixed-case\">mammalian target of rapamycin (mTOR)<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> N<\/jats:styled-content>imotuzumab (83\u00a0nmol\/L) downregulates <jats:styled-content style=\"fixed-case\">pTYR<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> pMAPK<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">pSTAT<\/jats:styled-content>3 by 40%, 20% and 30%, respectively. The combination, targeting these two different signaling hubs, may be associated with the synergistic inhibition observed. In vivo, the use of half human therapeutic equivalent doses for both the drugs substantially reduces tumors established in nude as well as <jats:styled-content style=\"fixed-case\">severe combined immunodeficiency (SCID)<\/jats:styled-content> mice by <jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content> overexpressing A\u2010431 cells. The drug combination reduces cell proliferation and the expression of signal transduction molecules. Treated tumors are better differentiated as compared with those established in the control mice. Tumor microarray demonstrates that <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>imotuzumab and the combination groups segregate independently to the <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>irolimus and the control treatment. The combination uniquely downregulated 55% of the altered tumor genes, extending beyond the typical pathways associated with <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>imotuzumab and <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>irolimus downstream pathways inhibition. These results would suggest that this nontoxic drug combination improves therapeutic benefit even in patients with low\u2010<jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content> expression and severely immunocompromised because of their current medication.<\/jats:p>","DOI":"10.1002\/cam4.21","type":"journal-article","created":{"date-parts":[[2012,8,2]],"date-time":"2012-08-02T13:06:41Z","timestamp":1343912801000},"page":"114-127","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>EGFR<\/scp> targeting monoclonal antibody combines with an <scp>mTOR<\/scp> inhibitor and potentiates tumor inhibition by acting on complementary signaling hubs"],"prefix":"10.1002","volume":"1","author":[{"given":"Roshan","family":"James","sequence":"first","affiliation":[{"name":"Biocon Ltd, R&amp;D Drug Development Group Bangalore 560100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siddharth","family":"Vishwakarma","sequence":"additional","affiliation":[{"name":"Biocon Ltd, R&amp;D Drug Development Group Bangalore 560100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Indira V.","family":"Chivukula","sequence":"additional","affiliation":[{"name":"Biocon Ltd, R&amp;D Drug Development Group Bangalore 560100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chetana","family":"Basavaraj","sequence":"additional","affiliation":[{"name":"Clinigene International Ltd Bangalore 560100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramakrishnan","family":"Melarkode","sequence":"additional","affiliation":[{"name":"Biocon Ltd, R&amp;D Drug Development Group Bangalore 560100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Montero","sequence":"additional","affiliation":[{"name":"Center of Molecular Immunology Havana 11600 Cuba"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradip","family":"Nair","sequence":"additional","affiliation":[{"name":"Biocon Ltd, R&amp;D Drug Development Group Bangalore 560100 India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-06-0166"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.10.7.12793"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-0188"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405220101"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.1.1.7509"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-3042"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.6.9.4539"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.28.727"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.28.721"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1974"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.05.008"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.06.054"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb01045.x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106148"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.03.029"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0003"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2006.04.005"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2010.04235.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/82.13.1107"},{"key":"e_1_2_7_21_1","first-page":"39","article-title":"Sulforhodamine B assay and chemosensitivity","volume":"110","author":"Voigt W","year":"2005","journal-title":"Methods Mol. 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