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Gene expression profiling of B9 cells in response to two classes of BRAF inhibitors

ABSTRACT: Selective RAF inhibitors including vemurafenib (PLX4032) have demonstrated clinical efficacy in mutant BRAF driven metastatic melanoma. The clinical effectiveness of RAF inhibitors depends on near complete abolition of the MAPK pathway output in tumors harboring BRAF mutations. However these compounds paradoxically activate the MAPK pathway in cells bearing oncogenic RAS or elevated upstream receptor signaling. This paradox can promote cellular proliferation and can manifest clinically with progression of secondary malignancies such as cutaneous squamous cell carcinomas (cuSCC). We have identified next generation RAF inhibitors (“paradox breakers”, e.g. PLX7904) that inhibit mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In murine cuSCC B9 cells that express the same HRAS mutation prevalent in squamous tumors from patients treated with RAF inhibitors, the first-generation RAF PLX4032 stimulated in vitro and in vivo growth; by contrast the paradox breaker PLX7904 had no effect. Here we compared the gene expression changes in B9 cells treated overnight with PLX4032 and PLX7904.

ORGANISM(S): Mus musculus

PROVIDER: GSE71109 | GEO | 2015/10/01

SECONDARY ACCESSION(S): PRJNA290366

REPOSITORIES: GEO

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Project description:Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of plasma cells (PCs) in the bone marrow (BM). The genetic background and clinical course of the disease are largely heterogeneous, and MM pathophysiology ranges from the premalignant condition of monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM, symptomatic MM, and extramedullary MM/plasma cell leukemia (PCL). Recent genome-wide sequencing efforts have provided the rationale for molecularly aimed treatment approaches, identifying mutations that can be specifically targeted, such as those in the mitogen-activated protein kinase (MAPK) pathway, which represent the most prevalent mutations in MM. Among these, mutations affecting BRAF gene, detected in 4-15% of patients, are of potential immediate clinical relevance due to the availability of effective inhibitors of this serine-threonine kinase which are in fact being explored also in myeloma. In this study, we screened by next generation sequencing (NGS) a large and representative series of intramedullary and extramedullary MM patients, including primary and secondary plasma cell leukemia (pPCL and sPCL, respectively), for mutations in BRAF, NRAS and KRAS genes. We evaluated the relationship of identified variants with other clinical and biological features and determined the transcriptional signature associated with MAPK pathway activation in MM. To further elucidate the transcriptional programs modulated by BRAF activation in MM, we used the PLX4032 drug to inhibit BRAF activity in U266 human myeloma cell line (HMCL), carrying K601N mutation and showing constitutive activation of MEK/ERK signaling. After confirming its ability to suppress MAPK pathway and myeloma cell proliferation in culture in the U266 cell line, we investigated the specific modulation of gene expression induced by the drug. U266 cells were treated with PLX4032 (30 µM) or DMSO for 12 hours and subjected to gene expression profiling (GEP) analysis by using Affymetrix GeneChip Human Gene 1.0ST arrays.

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Gene expression profiling of B9 cells in response to two classes of BRAF inhibitors

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