Cellular mechanisms underlying complete hematological response of chronic myeloid leukemia to BRAF/MEK inhibition in a patient with concomitant metastatic melanoma

Andrews, MC; Turner, N; Boyd, J; Roberts, AW; Grigg, A; Behren, A; Cebon, JS

Author(s): Andrews, MC; Turner, N; Boyd, J; Roberts, AW; Grigg, A; Behren, A; Cebon, JS;
Details: Publication Year 2015-12-01,Volume 21,Issue #23,Page 5222-34
Journal Title: Clinical Cancer Research
Publication Type: Journal Article
Abstract: PURPOSE: 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 pre-clinical 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 hematological malignancies. EXPERIMENTAL DESIGN: We report a case of complete hematological 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-signalling. 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.
Publisher: American Association for Cancer Research
Research Division(s): Cancer And Haematology; Systems Biology And Personalised Medicine
PubMed ID: 26202951
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-15-0393
NHMRC Grants: NHMRC/637309, NHMRC/1016647,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-07-28 12:00:06

Last Modified: 2020-04-07 02:29:00