Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.

Abstract

UNLABELLED:

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 BRAF(V600E) 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 BRAF(V600E)-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 BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-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.

SIGNIFICANCE:

We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

• Authors: Eli L Diamond, Benjamin H Durham, Julien Haroche, Zhan Yao, Jing Ma, Sameer A Parikh, Zhaoming Wang, John Choi, Eunhee Kim, Fleur Cohen-Aubart, Stanley Chun-Wei Lee, Yijun Gao, Jean-Baptiste Micol, Patrick Campbell, Michael P Walsh, Brooke Sylvester, Igor Dolgalev, Olga Aminova, Adriana Heguy, Paul Zappile, Joy Nakitandwe, Chezi Ganzel, James D Dalton, David W Ellison, Juvianee Estrada-Veras, Mario Lacouture, William A Gahl, Philip J Stephens, Vincent A Miller, Jeffrey S Ross, Siraj M Ali, Samuel R Briggs, Omotayo Fasan, Jared Block, Sebastien Héritier, Jean Donadieu, David B Solit, David M Hyman, José Baselga, Filip Janku, Barry S Taylor, Christopher Y Park, Zahir Amoura, Ahmet Dogan, Jean-Francois Emile, Neal Rosen, Tanja A Gruber, Omar Abdel-Wahab
• Journal: Cancer discovery (Cancer Discov) Vol. 6 Issue 2 Pg. 154-65 (Feb 2016) ISSN: 2159-8290 [Electronic] United States
• PMID: 26566875 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases
• Receptor, trkA
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Anaplastic Lymphoma Kinase
• Gene Expression Profiling (methods)
• Histiocytosis, Langerhans-Cell (drug therapy, enzymology, genetics)
• Histiocytosis, Non-Langerhans-Cell (drug therapy, enzymology, genetics)
• Humans
• MAP Kinase Kinase 1 (genetics)
• MAP Kinase Signaling System (drug effects)
• Mutation
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Receptor Protein-Tyrosine Kinases (genetics)
• Receptor, trkA (genetics)
• Sequence Analysis, DNA (methods)