{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:15:35Z","timestamp":1788383735178,"version":"build-2803163510"},"reference-count":33,"publisher":"American Association for Cancer Research (AACR)","issue":"2","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The clinical experience with BCR\u2013ABL tyrosine kinase inhibitors (TKI) for the treatment of chronic myelogenous leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR\u2013ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR\u2013ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR\u2013ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR\u2013ABL-mediated oncogene addiction is facilitated by persistent high levels of MAP\u2013ERK kinase (MEK)-dependent negative feedback.<\/jats:p>\n                  <jats:p>Significance: We found that BCR\u2013ABL can confer addiction in vitro by rewiring myeloid GF-R signaling through establishment of MEK-dependent negative feedback. Our findings predict that deeper, more durable responses to targeted agents across a range of malignancies may be facilitated by maintaining negative feedback concurrently with oncoprotein inhibition. Cancer Discov; 4(2); 200\u201315. \u00a92013 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 131<\/jats:p>","DOI":"10.1158\/2159-8290.cd-13-0235","type":"journal-article","created":{"date-parts":[[2013,12,20]],"date-time":"2013-12-20T20:40:49Z","timestamp":1387572049000},"page":"200-215","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["MEK-Dependent Negative Feedback Underlies BCR\u2013ABL-Mediated Oncogene Addiction"],"prefix":"10.1158","volume":"4","author":[{"given":"Jennifer","family":"Asmussen","sequence":"first","affiliation":[{"name":"Authors' Affiliations: Departments of 1Pharmaceutical Sciences and Pharmacogenomics, 2Chemistry and Chemical Biology, 3Pharmaceutical Chemistry, 4Otolaryngology, and 5Epidemiology and Biostatistics; 6Division of Hematology\/Oncology; and 7Helen Diller Family Comprehensive Cancer Center, University of California, San 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2Chemistry and Chemical Biology, 3Pharmaceutical Chemistry, 4Otolaryngology, and 5Epidemiology and Biostatistics; 6Division of Hematology\/Oncology; and 7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma","family":"Burlingame","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Pharmaceutical Sciences and Pharmacogenomics, 2Chemistry and Chemical Biology, 3Pharmaceutical Chemistry, 4Otolaryngology, and 5Epidemiology and Biostatistics; 6Division of Hematology\/Oncology; and 7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles S.","family":"Craik","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Pharmaceutical Sciences and Pharmacogenomics, 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