Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

Abstract

Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of BRAFV600E mutations in ~50% of these patients provided the first molecular therapeutisc target in histiocytosis. However, recurrent driving mutations in the majority of BRAFV600E-wildtype, non-LCH patients are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in BRAFV600E-wildtype, non-LCH patients. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of MAP2K1- and ARAF-mutated, non-LCH patients using MEK and RAF inhibitors, respectively, resulted in clinical efficacy demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.

Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

“…Table 1 summarizes a literature review of gene mutations described in non-LCH, demonstrating the clear preponderance of kinase activating mutations involving the MAPK pathway. In particular, very recently, a study used whole-exome sequencing, RNA-seq, and targeted sequencing techniques to describe several recurrent gene mutations and fusions in LCH and non-LCH (including Touton'' type giant cells; the histiocytes were immunoreactive for e S100, f CD68, and g FXIIIa RDD) [34]. Interestingly, that study also found mean variant allele frequencies at levels similar to our study, including a KRAS G12D missense variant in RDD.…”

“…Further mutational studies on this rare histiocytic disease should be undertaken to better characterize its pathogenesis as well as open up potential avenues for therapy. BRAF (p.V600E) [7][8][9] PIK3CA (p.E542K, p.E545K, p.A1046T, and p.H1047R) [7,34] NRAS (p.G12D, p.Q61K, p.Q61R) [7,34] KRAS (p.G12S) [34] MAP2K1 (p.K57E/N, p.Q56P, p.F68L, p.S123T/P, p.E144K, p.E51_Q58del, p.Q58_E62del, p.E102_I103del) [34] ARAF (p.S214A, p.A225 V, p.P539H) [34] BRAF fusions (RNF11-BRAF, CLIP2-BRAF) [34] KIF5B-ALK fusion [34] LMNA-NTRK fusion [34] Rosai-Dorfman disease (RDD) NRAS (p.Q61R) [34] KRAS (p.G12D) [34] SMAD4 (p.T521I) [40] MAP2K1 (p.V60M, p.D65M) [34] ARAF (p.N217K) [34] Juvenile xanthogranuloma (JXG) NRAS (p.Q61R) [34] KRAS (p.G12D) [34] MAP2K1 (p.T28I, p.L37P, p.E120Q, p.Y130C) [34] ARAF (p.N217K, p.F351L) [34] Histiocytic sarcoma BRAF (p.V600E) [8] PTEN deletion (deletion involving exon 7 (c.635-7_639del) [37], exon 6-9 [41] …”

Tocilizumab in patients with multisystem Erdheim–Chester disease

“…For example, molecular studies may allow the identification of mutations amenable to target therapy with small molecule inhibitors. 8 As part of this effort in dissecting and contrasting the molecular and genetic bases of ECD, combination therapy with small molecules and anti-cytokine agents is particularly appealing, as it may be effective against both the oncogenic transformation and inflammatory activation.…”

“…Tocilizumab was administered intravenously at a standard dose of 8 mg/kg at time 0, and at weeks 4,8,12,16,20, and 24 ( Fig. 1).…”

“…6,7 Recent evidence indicates that deregulated activation of the mitogen-activated protein kinase (MAPK) pathway due to oncogenic mutations in the BRAF, NRAS, PIK3CA, and MAP2K1 genes is central to the pathogenesis of ECD. [8][9][10] Following these discoveries, treatment with small-molecule inhibitors of BRAF V600E (vemurafenib) or MEK (cobimetinib, trametinib) came to fruition (reviewed in 11 ). However, there are several concerns regarding the safety and tolerability of long-term treatment, as these agents are often associated with severe or life-threatening adverse effects, 12 while unequivocal therapy end-points and maintenance regimens are yet to be identified.…”