title: Cellular Mechanisms Underlying Complete Hematological Response of Chronic Myeloid Leukemia to BRAF and MEK1/2 Inhibition in a Patient with Concomitant Metastatic Melanoma.
abstract: OBJECTIVE
  Targeted MEK inhibition is an emerging therapy in a number of solid tumors. It holds particular promise in BRAF V600E mutation-positive malignant melanoma, where constitutive activation and cell growth through the MAP kinase (MAPK) pathway is well established. In vitro and preclinical research indicates that MAPK pathway activation is important in chronic myeloid leukemia (CML) leukemogenesis; however, the potential of MEK inhibition has not yet been investigated clinically in the setting of such hematologic malignancies.
  
  
  METHODS
  We report a case of complete hematologic response of CML to MEK inhibition in a patient with synchronous metastatic melanoma, who received treatment with combination BRAF and MEK1/2 inhibitors. We studied the effects of these agents on proliferation and outgrowth of myeloid precursors, and longitudinal shifts in peripheral blood phenotyping during the course of treatment. A model cell line system was used to examine the effects of dabrafenib and trametinib on MAPK and BCR-ABL1 signaling.
  
  
  RESULTS
  After 35 weeks on treatment with BRAF and MEK inhibitors, complete hematologic response was observed without recourse to BCR-ABL1-targeted therapy. MEK inhibition was principally responsible for impaired proliferation of both mature and primitive myeloid precursors, as well as growth and hemoglobinization of erythroid precursors. Paradoxical activation of the MAPK pathway was seen in response to BRAF inhibitor therapy but this was easily overcome by clinically relevant doses of concurrent MEK inhibitor.
  
  
  CONCLUSIONS
  These studies suggest that further evaluation of the optimal MAPK targeting approach is warranted to extend therapeutic options in CML.
authors.affiliation: Medical Oncology, Austin Health, Austin Hospital, Heidelberg, Victoria, Australia. Ludwig Institute for Cancer Research, Austin Branch, Heidelberg, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Miles C
authors.initials: MC
authors.lastname: Andrews
authors.affiliation: Medical Oncology, Austin Health, Austin Hospital, Heidelberg, Victoria, Australia. Ludwig Institute for Cancer Research, Austin Branch, Heidelberg, Victoria, Australia. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Turner
authors.affiliation: Clinical Haematology and Bone Marrow Transplantation, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Janis
authors.initials: J
authors.lastname: Boyd
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. Clinical Haematology and Bone Marrow Transplantation, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia. Haematology, Austin Health, Austin Hospital, Heidelberg, Victoria, Australia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Grigg
authors.affiliation: Ludwig Institute for Cancer Research, Austin Branch, Heidelberg, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Behren
authors.affiliation: Medical Oncology, Austin Health, Austin Hospital, Heidelberg, Victoria, Australia. Ludwig Institute for Cancer Research, Austin Branch, Heidelberg, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. jonathan.cebon@onjcri.org.au.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000556:secondary* / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D009382:Neoplasms, Unknown Primary; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016044:Fusion Proteins, bcr-abl; D048493:Proto-Oncogene Proteins B-raf