Shifting ecologies of malignant and nonmalignant cells following BRAF inhibition
Catherine J. Wu
Catherine J. Wu
Published November 3, 2014; First published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):4681-4683. https://doi.org/10.1172/JCI78783.
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Category: The Attending Physician

Shifting ecologies of malignant and nonmalignant cells following BRAF inhibition

Abstract

Clinical vignette: A 49-year-old man with stage IV BRAFV600E-driven melanoma was initiated on twice-daily 960 mg of vemurafenib for treatment of progressive and recurrent subcutaneous metastatic disease of the left lower extremity. The patient’s melanoma responded well to targeted BRAF inhibition. At treatment onset, hematologic parameters were all within normal limits; however, within three months of initiating therapy, wbc were found to be elevated (to 20 K) with sustained lymphocytosis of mature phenotype. Immunophenotypic analysis was consistent with chronic lymphocytic leukemia (CLL), and FISH results revealed presence of the CLL-associated deletion in chromosome 13q14 as well as in 2p33. Vemurafenib was withdrawn after approximately one year of therapy, and subsequently, his peripheral lymphocytosis resolved and CLL regressed. Nevertheless, a monoclonal B cell population persisted even 732 days after discontinuation of vemurafenib.

Authors

Catherine J. Wu

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Figure 1

Shifting ecologies with vemurafenib exposure.

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Shifting ecologies with vemurafenib exposure. (A) The mechanism of proli...
(A) The mechanism of proliferation and survival through the MAPK signaling pathway in melanoma and CLL/MBL. In mutated BRAF+ melanoma, this pathway is constitutively activated through the effects of the V600E mutation, which is strongly activating. Exposure to BRAF-inhibiting agents, such as vemurafenib, disables this pathway, leading to cell death. CLL and MBL have autonomous BCR signaling. In the setting of BRAF inhibition, drug-bound BRAF and BCR/SYK-activated RAS cooperatively induce paradoxical ERK activation in CLL cells, leading to proliferation and survival. (B) Schematic representation of the temporal association between the development of B cell lymphocytosis/CLL with vemurafenib exposure and its regression with removal of the pharmacologic agent.