Internal medicine

Disease

Protein-Tyrosine Kinases

Histiocyte

Biology

Receptor tyrosine kinase

Kinase

Malignant pleural effusion

Immunology

Pleural effusion

Histiocytic sarcoma

Erdheim–Chester disease

Histiocytosis

Crizotinib

MAPK/ERK pathway

Signal transduction

Tyrosine kinase

Cancer research

Genetics

Medicine

Nature Medicine

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis. Inhibition of CSF-1R with recurrent activating alterations and other actionable targets identified by genomic sequencing elicits clinical activity in patients with histiocytosis.

Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms