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Identification of RSPO2 Fusion Mutations and Target Therapy Using a Porcupine Inhibitor

Chong Li1, Jing Cao1, Ning Zhang1

  • 1Pharmacy School, Shanghai Jiaotong University, Shanghai, 200240, China.

Scientific Reports
|September 26, 2018
PubMed

Insights

New R-Spondin 2 (RSPO2) gene fusions drive digestive system cancers. Wnt pathway inhibitors effectively treated these RSPO2 fusion tumors, showing promise as a targeted therapy and biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Somatic gene mutations drive cancer development, necessitating novel targeted therapies.
  • The Wnt signaling pathway is implicated in various cancers and is a target for inhibitor drugs.
  • Identifying specific genetic abnormalities can guide the development of effective cancer treatments.

Purpose of the Study:

  • To identify Wnt pathway-related gene abnormalities sensitive to Wnt inhibitor treatment.
  • To investigate novel transcript fusions involving R-Spondin 2 (RSPO2) in digestive system cancers.
  • To evaluate the oncogenic potential of RSPO2 fusions and their response to Wnt pathway inhibition.

Main Methods:

  • Analysis of Patient Derived Xenograft (PDX) RNA samples to detect gene fusions.
  • Identification of RSPO2 transcript fusions with EMC2, PVT1, and HNF4G genes.
  • Assessment of RSPO2-EMC2 fusion oncogenic effects in mouse models.
  • Treatment of PDX mouse models with a Wnt pathway Porcupine inhibitor (CGX1321).

Main Results:

  • Novel RSPO2 transcript fusions were identified in approximately 1.4% of digestive system cancer samples.
  • The RSPO2-EMC2 fusion was confirmed to drive oncogenesis, tumor growth, and metastasis.
  • All tested RSPO2 fusion-bearing tumors showed complete response and halted progression upon treatment with CGX1321.

Conclusions:

  • Wnt pathway inhibition is a potentially effective treatment strategy for cancers harboring RSPO2 fusions.
  • RSPO2 fusions can serve as a predictive biomarker for patient selection in Wnt inhibitor therapy for digestive system cancers.
  • Targeting RSPO2 fusions represents a promising approach for precision medicine in oncology.

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