{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T11:49:24Z","timestamp":1774266564794,"version":"3.50.1"},"reference-count":56,"publisher":"Proceedings of the National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,9,13]]},"abstract":"<jats:p>\n                    The PI3K pathway is frequently activated in cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, particularly the hallmark oncogene PIK3CA. Although targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3K\/mammalian target of rapamycin (mTOR) inhibitor BEZ235, and by genome-wide copy number analyses, we identified\n                    <jats:italic>MYC<\/jats:italic>\n                    and\n                    <jats:italic>eIF4E<\/jats:italic>\n                    amplification within the resistant cells. Importantly, either MYC or eukaryotic translation initiation factor 4E (eIF4E) was required to bypass pharmacological PI3K\/mTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5\u2032 cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K pathway-targeted drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1108237108","type":"journal-article","created":{"date-parts":[[2011,8,29]],"date-time":"2011-08-29T22:04:21Z","timestamp":1314655461000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":183,"title":["PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis"],"prefix":"10.1073","volume":"108","author":[{"given":"Nina","family":"Ilic","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Dana\u2013Farber Cancer Institute, and"}]},{"given":"Tamara","family":"Utermark","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana\u2013Farber Cancer Institute, and"}]},{"given":"Hans R.","family":"Widlund","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115"}]},{"given":"Thomas M.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana\u2013Farber Cancer Institute, and"}]}],"member":"341","published-online":{"date-parts":[[2011,8,29]]},"reference":[{"key":"e_1_1_2_17_9_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.296.5573.1655"},{"key":"e_1_1_2_17_9_2_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1385"},{"key":"e_1_1_2_17_9_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802785105"},{"key":"e_1_1_2_17_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(02)86001-8"},{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"5497","DOI":"10.1038\/onc.2008.245","article-title":"PI3K pathway alterations in cancer: Variations on a theme","volume":"27","author":"Yuan TL","year":"2008","unstructured":"TL Yuan, LC Cantley, PI3K pathway alterations in cancer: Variations on a theme. Oncogene 27, 5497\u20135510 (2008).","journal-title":"Oncogene"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.ccr.2005.05.014","article-title":"Mutant PIK3CA promotes cell growth and invasion of human cancer cells","volume":"7","author":"Samuels Y","year":"2005","unstructured":"Y Samuels, et al., Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561\u2013573 (2005).","journal-title":"Cancer Cell"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1126\/science.1096502","article-title":"High frequency of mutations of the PIK3CA gene in human cancers","volume":"304","author":"Samuels Y","year":"2004","unstructured":"Y Samuels, et al., High frequency of mutations of the PIK3CA gene in human cancers. 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