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MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Asmussen, Jennifer Lasater, Elisabeth A. Tajon, Cheryl A. Oses-Prieto, Juan A. Jun, Young-Wook Taylor, Barry S. Burlingame, Alma Craik, Charles S. Shah, Neil Pravin |
| Copyright Year | 2014 |
| Abstract | UNLABELLED The clinical experience with BCR-ABL 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-ABL 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-ABL-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 BRAF(V600E) in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated oncogene addiction is facilitated by persistent high levels of MAP-ERK kinase (MEK)-dependent negative feedback. SIGNIFICANCE We found that BCR–ABL 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. |
| Starting Page | 10474 |
| Ending Page | 10480 |
| Page Count | 7 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerdiscovery.aacrjournals.org/content/candisc/4/2/200.full.pdf |
| Alternate Webpage(s) | http://cancerdiscovery.aacrjournals.org/content/candisc/early/2013/12/20/2159-8290.CD-13-0235.full.pdf |
| Alternate Webpage(s) | http://nsmn1.uh.edu/frankino/assets/docs/lifesciseries/asmussen/asmussen.pdf |
| Alternate Webpage(s) | http://www.craiklab.ucsf.edu/docs/pub287.pdf |
| PubMed reference number | 24362263v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/2159-8290.CD-13-0235 |
| DOI | 10.1158/2159-8290.cd-13-0235 |
| Journal | Cancer discovery |
| Volume Number | 4 |
| Issue Number | 2 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Addictive Behavior BCR gene BCR protein, human Biospecimen Core Resource Facility Chronic Lymphocytic Leukemia Fusion Proteins, bcr-abl Growth Factor Receptors Ligands Myeloid Leukemia Myeloid Leukemia, Chronic Oncogene Proteins Oncogenes Protein Tyrosine Kinase Proto-Oncogene Proteins c-fes Signal Transduction Pathways Tyrosine Kinase Inhibitors [MoA] abl Oncogene erbB-2 Receptor |
| Content Type | Text |
| Resource Type | Article |
