Histiocytic lesions are characterised by aberrant accumulation and proliferation of histiocytic lineage cells, often driven by oncogenic signalling pathways, creating actionable therapeutic vulnerabilities. In this context, BRAF inhibition with vemurafenib (VEM) is a rational targeted strategy, but its effects on cell-cycle control and stress adaptation in histiocytes are unknown. The aim of the study was to determine whether VEM promotes cell-cycle arrest and senescence-like responses in a primary cell culture derived from histiocytic lesions, and to characterise accompanying transcriptional changes at sublethal (IC25) and inhibitory (IC50) concentrations.

Experiments were performed using the RAB-1 primary cell line derived from histiocytic lesions (DSM ACC3377; patent application: P.447749). The impact of VEM at IC25 and IC50 on cell-cycle distribution was evaluated using a cytometric approach with the FxCycle PI/RNase Staining Solution (Thermo Fisher). In parallel, the dose-dependent transcriptional response to VEM was profiled using the Human Cancer PathwayFinder RT² Profiler PCR Array (QIAGEN) covering key cancer pathways, including proliferation, cell-cycle control, senescence/SASP, stress/DNA damage response, and pro-survival adaptation.

The obtained results showed that VEM shifts RAB-1 cells towards G0/G1 arrest at both IC25 and IC50. Transcriptional profiling revealed a consistent decrease in the proliferation marker MKI67 and downregulation of SERPINB2, linked to inflammatory signalling and reported in senescence/SASP-associated transcriptional signatures in selected models. In parallel, stress and DNA damage response-related genes (GADD45G, DDIT3, MAP2K3) were upregulated in a dose-dependent manner. Notably, sustained induction of cytoprotective and anti-apoptotic transcripts (HMOX1, XIAP, TBX2) suggests an adaptive survival programme that may be compatible with senescent-cell persistence.

Vemurafenib reshapes the transcriptional landscape of primary histiocytic lesion–derived cells (RAB-1 cell line) by attenuating proliferative programmes and engaging stress-adaptation pathways. These molecular changes and G0/G1 arrest may represent a key component of VEM-induced adaptation. However, further studies integrating molecular profiling with metabolic and functional assays are warranted to clarify these mechanisms and to inform rational optimisation of therapeutic strategies for histiocytic disorders.

Project no. 2019/ABM/01/000164 (POLHISTIO) financed by the Medical Research Agency.