title: MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Asmussen
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lasater
authors.forename: Cheryl
authors.initials: C
authors.lastname: Tajon
authors.forename: Juan
authors.initials: J
authors.lastname: Oses-Prieto
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Jun
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Alma
authors.initials: A
authors.lastname: Burlingame
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D000069439:Dasatinib; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040901:Proteomics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017467:Receptors, Erythropoietin; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D000069439:Dasatinib