Targeting the Mutational Landscape of Bystander Cells: Drug-Promoted Blood Cancer From High-Prevalence Pre-neoplasias in Patients on BRAF Inhibitors.

Donjete Simnica,Carsten Bockemeyer,Alexander Stein,Mascha Binder,Harald Ittrich

doi:10.3389/fonc.2020.540030

Abstract

Drug-promoted cancers are increasingly recognized as a serious clinical problem in patients receiving BRAF inhibitory treatment. Here we report on a patient with BRAF mutant hairy cell leukemia and monoclonal B-cell lymphocytosis (MBL), who responded durably to BRAF/MEK inhibitors (BRAFi/MEKi) but experienced transformation of a RAS mutant MBL to chronic lymphocytic leukemia (CLL) with accelerated nodal progression. Hypothesizing that BRAFi triggered excessive MEK-ERK signaling in the MBL/CLL clone via the CRAF/RAS complex as previously described for BRAFi-induced cancers, BRAFi was discontinued inducing a rapid remission of the CLL on MEKi alone. Liquid biopsy monitoring showed a continuous increase of the MBL/CLL clone from the start of BRAFi/MEKi treatment followed by a rapid decline upon BRAFi withdrawal. Next-generation sequencing of a cohort of patients with MBL and monoclonal gammopathy of unclear significance (MGUS) revealed that almost one third of these cases harbored RAS mutations. In view of the population frequency of lymphatic pre-malignant conditions and the prevalence of RAS mutations in such cases, vigilant surveillance remains critical in patients treated with BRAF inhibitors.

Highlights

Activating BRAF mutations, providing oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway, are the key molecular driver in a variety of solid tumors including roughly 50% of malignant melanomas, 15% of thyroid cancers, 8% of colorectal cancers, 3% of lung cancers, and 2% of pancreatic cancers
We found that the initial monoclonal B-cell lymphocytosis (MBL) clone as well as the emerging chronic lymphocytic leukemia (CLL) carried an activating KRAS G12D mutation, but no BRAF mutation, explaining the observed CLL progression
Since enhanced MAPK signaling was expected to be attenuated upon withdrawal of the BRAF inhibitors (BRAFi), treatment was continued with the MEK inhibitors (MEKi) only, inducing a nodal CLL decline with maintained hairy cell leukemias (HCL) control (Figure 1A)

Summary

Introduction

Activating BRAF mutations (most prominently BRAF V600E), providing oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway, are the key molecular driver in a variety of solid tumors including roughly 50% of malignant melanomas, 15% of thyroid cancers, 8% of colorectal cancers, 3% of lung cancers, and 2% of pancreatic cancers. Despite the fact that BRAF is a key effector downstream of RAS and upstream of MEK, ATP-competitive BRAFi are not effective in RAS mutant tumor models [2] Such inhibitors have opposing effects on MAPK signaling depending on the BRAF mutational status. In tumor and normal cells expressing wild-type BRAF, these inhibitors have been found to promote BRAF dimerization, activation and binding to RAS-GTP, resulting in stimulation of MEK-ERK signaling and proliferative effects [3, 4] This paradoxical activation is thought to explain why this class of drugs may induce or promote RAS mutant neoplasias which emerges as a more and more serious clinical problem the more patients are offered this targeted treatment approach [5,6,7,8,9,10,11,12]

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Conclusion