RAS pathway targeted therapy in patients with DICER1-associated sarcomas

Abstract

DICER1-associated sarcomas commonly exhibit cooperating mutations involving RAS signaling pathways, but the efficacy of therapies that target these mutations is unknown. Here we report two children with DICER1 tumor predisposition who presented with DICER1-associated sarcomas with cooperating, targetable mutations in HRAS or BRAF. Both had relapsed/progressed disease despite upfront multimodal therapy and were subsequently treated with molecularly targeted agents. In the first case, mutant BRAF became amplified after dual dabrafenib/trametinib therapy, presumably as a driver of acquired resistance. In the second case, a subclonal HRAS variant at diagnosis became the predominant clone at autopsy, suggesting its importance in therapy resistance. Together, these two cases provide molecular evidence of the significance of RAS/ERK signaling in DICER1-driven tumorigenesis and highlight the potential for targeting these cooperating mutations.

Fig. 1. Timeline of the clinical course for each patient.

A Patient 1, with DICER1-associated sarcoma and BRAF p.V600E; and B Patient 2, with pleuropulmonary blastoma and HRAS p.G13R. MRI imaging at key timepoints is shown, including available imaging during treatment with molecularly targeted agents (dabrafenib/ trametinib, Patient 1; trametinib, Patient 2) as indicated. Yellow arrows indicate tumor location. Orange arrows indicate surgical intervention.

Fig. 2. BRAF amplification was assessed using FFPE interphase FISH.

Red signals represent the BRAF gene (7q34), and green signals correspond to the chromosome 7 centromere probe (D7Z1). A, B No BRAF amplification (copy-neutral status) is observed in interphase FISH of the initial diagnosis specimen (A) or a specimen collected 14 months later (B). C Interphase FISH demonstrates BRAF amplification, with more than ten red signals corresponding to the BRAF gene (7q34) per cell, alongside two green signals indicating two copies of the chromosome 7 centromere.