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RAS pathway targeted therapy in patients with DICER1-associated sarcomas.

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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.

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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.