RAS pathway targeted therapy in patients with DICER1-associated sarcomas
Lindy Zhang1, Paige H R Mallinger2,3, Serena Zhou4
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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.
Insights
DICER1-associated sarcomas often have RAS pathway mutations. Targeted therapies showed potential but also resistance mechanisms, with BRAF amplification and HRAS variant evolution observed in two pediatric cases.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- DICER1-associated sarcomas frequently involve RAS signaling pathway mutations.
- The effectiveness of therapies targeting these cooperating mutations in DICER1 sarcomas remains largely unknown.
Purpose of the Study:
- To investigate the efficacy of molecularly targeted agents in pediatric patients with DICER1-associated sarcomas harboring HRAS or BRAF mutations.
- To explore potential mechanisms of acquired resistance to targeted therapies in these tumors.
Main Methods:
- Case report of two children with DICER1 tumor predisposition and DICER1-associated sarcomas.
- Treatment with molecularly targeted agents (dabrafenib/trametinib) for relapsed/progressed disease.
- Molecular analysis to identify mutations and track clonal evolution, including BRAF amplification and HRAS variant dynamics.
Main Results:
- The first patient developed BRAF amplification following dual dabrafenib/trametinib therapy, suggesting acquired resistance.
- In the second patient, a subclonal HRAS variant present at diagnosis became the predominant clone by autopsy, indicating its role in therapy resistance.
- Both cases demonstrated targetable HRAS or BRAF mutations cooperating with DICER1 alterations.
Conclusions:
- RAS/ERK signaling plays a significant role in DICER1-driven tumorigenesis.
- Targeting cooperating RAS pathway mutations in DICER1-associated sarcomas is a potential therapeutic strategy.
- Understanding resistance mechanisms, such as BRAF amplification and clonal evolution of HRAS variants, is crucial for optimizing treatment.
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