Abstract
Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high-throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling. Both mutations were previously reported in human histiocytic sarcoma. Trametinib inhibited sensitive cell lines by promoting cell apoptosis, indicated by a significant increase in caspase 3/7. Furthermore, in vitro findings were successfully recapitulated in an intrasplenic orthotopic xenograft mouse model, which represents a disseminated aggressive form of histiocytic sarcoma. Mice with histiocytic sarcoma xenograft neoplasms that were treated with trametinib had significantly longer survival times. Target engagement was validated as activity of ERK, downstream of MEK, was significantly downregulated in neoplasms of treated mice. Additionally, trametinib was found in plasma and neoplastic tissues within projected therapeutic levels. These findings demonstrate that in dogs, histiocytic sarcoma may be associated with a dysfunctional MAPK pathway, at least in some cases, and may be effectively targeted through MEK inhibition. Clinical trials to test safety and efficacy of trametinib in dogs with histiocytic sarcoma are warranted, and may provide valuable translational information to similar diseases in humans. Mol Cancer Ther; 17(11); 2439-50. ©2018 AACR.
Highlights
Histiocytic and dendritic cell neoplasms encompass a group of proliferative entities with variable clinical behaviors and prognosis in humans [1]
We identified that the KRAS Q61H mutation is present in the OD cell line
Our findings provide further support that the MAPK pathway may represent an important oncogenic driver in canine histiocytic sarcoma (HS) and provide proof-of-concept data for initiating clinical trials with trametinib in dogs with HS
Summary
Histiocytic and dendritic cell neoplasms encompass a group of proliferative entities with variable clinical behaviors and prognosis in humans [1]. Histiocytic sarcoma (HS) is by far the most aggressive disorder with the worst prognosis [2]. It is a rare hematologic malignancy (
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