Data from Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

Abstract

<div>Abstract<p>Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of <i>BRAF</i><sup>V600E</sup> mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with <i>BRAF</i><sup>V600E</sup>–wild-type non-LCH 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 <i>BRAF, ALK</i>, and <i>NTRK1</i>, as well as recurrent, activating <i>MAP2K1</i> and <i>ARAF</i> mutations in patients with <i>BRAF</i><sup>V600E</sup>–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with <i>MAP2K1</i>- and <i>ARAF</i>-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.</p><p><b>Significance:</b> We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating <i>ARAF</i> and <i>MAP2K1</i> mutations in non-Langerhans histiocytic neoplasms. Refractory patients with <i>MAP2K1</i>- and <i>ARAF</i>-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. <i>Cancer Discov; 6(2); 154–65. ©2015 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 109</p></div>